Calquence Drug Information
Generic name: ACALABRUTINIB
Kinase Inhibitor [EPC]
Uses of Calquence
Previously Untreated Mantle Cell Lymphoma CALQUENCE in combination with bendamustine and rituximab is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT).
Previously Treated Mantle Cell Lymphoma CALQUENCE is indicated for the treatment of adult patients with MCL who have received at least one prior therapy.
Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Dosage & Administration of Calquence
Recommended Dosage CALQUENCE Administration Instructions
Advise patients to swallow tablet whole with water. Advise patients not to chew, crush, dissolve, or cut the tablets. CALQUENCE may be taken with or without food.
If a dose of CALQUENCE is missed by more than 3 hours, it should be skipped, and the next dose should be taken at its regularly scheduled time. Extra tablets of CALQUENCE should not be taken to make up for a missed dose. CALQUENCE as Monotherapy For patients with MCL, CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.
CALQUENCE in Combination with Bendamustine and Rituximab For patients with previously untreated MCL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE on Day 1 of Cycle 1 (each cycle is 28 days) and administer until disease progression or unacceptable toxicity. Start CALQUENCE at Cycle 1 (each cycle is 28 days).
Start obinutuzumab at Cycle 2 for a total of 6 cycles and refer to the obinutuzumab prescribing information for recommended dosing. Administer CALQUENCE prior to obinutuzumab when given on the same day. CALQUENCE in Combination with Venetoclax For patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression, unacceptable toxicity or completion of 14 cycles of treatment.
Start venetoclax at Cycle 3 for total of 12 cycles. Start venetoclax at 20 mg daily for first week of treatment and increase weekly as per dosing schedule for 5-week ramp up (up to 400 mg daily) as described in the venetoclax USPI. Refer to the venetoclax USPI for additional details.
Recommended Dosage for Drug Interactions Dosage Modifications for Use with CYP3A Inhibitors or Inducers These are described in Table 1. Table 2: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE Monotherapy and CALQUENCE in Combination with Obinutuzumab Table 3: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with BR Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Receiving CALQUENCE in Combination with Venetoclax Refer to the prescribing information of each of the products used in combination with CALQUENCE for additional information for management of toxicities.
| CYP3A | Co-administered Drug | Recommended CALQUENCE use |
|---|---|---|
| Inhibition | Strong CYP3A inhibitor | Avoid co-administration. If these inhibitors will be used short-term (such as anti‑infectives for up to seven days), interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE. |
| Moderate CYP3A inhibitor | Reduce the CALQUENCE 100 mg every 12 hours dosage to 100 mg once daily. | |
| Induction | Strong CYP3A inducer | Avoid co-administration. If co-administration is unavoidable, increase CALQUENCE dosage to 200 mg approximately every 12 hours. |
| Event | Adverse Reaction Occurrence | Dosage Modification (Starting dose = 100 mg approximately every 12 hours) |
|---|---|---|
| Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days | First and Second | Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours. |
| Third | Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at a reduced frequency of 100 mg once daily. | |
| Fourth | Discontinue CALQUENCE. | |
| Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). | ||
| Adverse Reaction | Severity a | Dosage Modification (Starting dosage of CALQUENCE = 100 mg approximately every 12 hours) |
|---|---|---|
| Neutropenia b [see Warnings and Precautions (5.3) ] | Absolute neutrophil count less than 0.5 x 10 9 /L for greater than 7 days | Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2, resume CALQUENCE at starting dosage. Upon 2nd or 3rd occurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Discontinue CALQUENCE at 4th occurrence. For bendamustine b: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2, resume bendamustine and consider dosage reduction to 70 mg/m 2.d,e |
| Thrombocytopenia f [see Warnings and Precautions (5.3) ] | Platelet count 25 to 50 x 10 9 /L with clinically significant bleeding or platelet count less than 25 x 10 9 /L | Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Consider discontinuing CALQUENCE at 3rd occurrence. For bendamustinef: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m 2.e |
| Non-hematologic adverse reactions [see Warnings and Precautions (5) ] | Grade 3 or higher | Interrupt CALQUENCE. Once toxicity has resolved to Grade ≤ 2 or baseline, resume CALQUENCE at starting dosage. If recurrence, reduce dosage of CALQUENCE to 100 mg once daily. c Discontinue CALQUENCE at 3rd occurrence of Grade 4 toxicity. For Grade 3 toxicity, consider the risks and benefits of continuing CALQUENCE. For bendamustine: Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or baseline, resume bendamustine and consider dose reduction to 70 mg/m 2.e |
| a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. b For neutropenia with ANC less than 1 x 10 9 /L, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m 2 may be appropriate in certain circumstances. c Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. d Consider use of myeloid growth factors before bendamustine dosage reduction. e Consider discontinuing bendamustine if additional dosage reduction is required. f For thrombocytopenia, a platelet count below 50 x 10 9 /L should prompt bendamustine dose interruption even in the absence of clinically significant bleeding. | ||
| Adverse Reactiona | Adverse Reaction Occurrence | Dose Modification |
| Grade 3 or 4 neutropenia with or without fever and/or infection; Grade 4 neutropenia lasting more than 7 days | First occurrence | Interrupt CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade ≤ 1 or baseline, restart CALQUENCE and/or venetoclax at same dose. |
| Second occurrence | Interrupt CALQUENCE and/or venetoclax.b Once toxicity resolves to Grade ≤ 1 or baseline, restart CALQUENCE at same dose and venetoclax at one lower dose levelc. | |
| Subsequent occurrence | Withhold CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1 or baseline.b,d | |
| Grade 3 or 4 thrombocytopenia and/or bleedingf | First occurrence | Interrupt CALQUENCE and/or venetoclax. When bleeding resolves and thrombocytopenia is Grade ≤ 1 or baseline without transfusion support for 5 consecutive days, restart CALQUENCE and/or venetoclax at same dose. |
| Second occurrence | Interrupt CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart CALQUENCE at same dose and/or restart venetoclax at one lower dose level.e | |
| Subsequent occurrences of severe thrombocytopenia | Interrupt CALQUENCE and venetoclax until resolution of bleeding and thrombocytopenia resolves to Grade ≤ 1 or baseline. Restart CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level.c,d,e | |
| Grade 3 or 4 tumour lysis syndrome (TLS) | First and subsequent episodes | If a subject experiences blood chemistry changes suggestive of TLS, the following day’s venetoclax and acalabrutinib dose should be withheld. If resolved within 24–48 hours of last dose, treatment can be resumed at the same dose. For events of clinical TLS or blood chemistry changes requiring more than 48 hours to resolve, venetoclax should be resumed at one lower dose level.c When resuming treatment after interruption due to TLS, monitor for TLS and provide prophylaxis. |
| Grade 3 other non-hematologic eventsg | First occurrence | Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1. Restart CALQUENCE and/or venetoclax at same dose. |
| Second occurrence | Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1d. | |
| Grade 4 other non-hematologic eventsg | First occurrence | Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1. Restart CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level.c, e |
| Second occurrence | Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤ 1d. | |
| a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Growth factor may be used at physician discretion. c See venetoclax USPI for dose level reductions details. d Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with CALQUENCE in combination with venetoclax. e CALQUENCE dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks. f Platelets may be used at physician discretion. g Certain treatment-emergent non-hematologic AEs (e.g., venous thromboembolic events) may be managed and become clinically stable following medical intervention but may not improve to Grade ≤ 1 according to the NCI CTCAE definitions. In such cases, if a subject is clinically stable, resumption of CALQUENCE may be possible based on clinical judgement of the treating physician. | ||
Side Effects of Calquence
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every 12 hours in 2,055 patients with hematologic malignancies. Among these recipients of CALQUENCE, 89% were exposed for at least 6 months and 82% were exposed for at least one year.
Previously Untreated Mantle Cell Lymphoma The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without BR) in patients with MCL. ECHO The safety of CALQUENCE in combination with bendamustine and rituximab (CALQUENCE plus BR) was evaluated in 297 patients with previously untreated MCL in ECHO. The trial enrolled patients with previously untreated MCL, ≥ 65 years of age with no intention for transplant, total bilirubin ≤ 1.5 × ULN, AST or ALT ≤ 2.5 × ULN, and estimated creatinine clearance of > in combination with bendamustine and rituximab.
Patients then received CALQUENCE 100 mg orally twice daily or placebo continuously until progressive disease or unacceptable toxicity, with 12 additional dosages of rituximab every other cycle up to Cycle 30. The median duration of treatment with CALQUENCE was 28.6 months. Serious adverse reactions occurred in 69% of patients who received CALQUENCE plus BR.
Fatal adverse reactions that occurred within 30 days of the last study treatment were reported in 12% who received CALQUENCE plus BR including %. Adverse reactions led to permanent discontinuation of CALQUENCE in 43%, dosage interruptions in 74%, and dosage reductions in 10% of patients. Adverse reactions that resulted in dosage modification in > 10% included infections, cytopenias, rashes, and gastrointestinal toxicity.
Adverse reactions which resulted in permanent discontinuation of CALQUENCE in ≥ 4% of patients included COVID-19 (includes COVID-19 pneumonia) and neutropenia. Table 5 and Table 6 summarize select adverse reactions and laboratory abnormalities observed in patients treated in ECHO. Table 5: Adverse Reactions* (≥ 15%) in Patients with Previously Untreated MCL Who Received CALQUENCE plus BR in ECHO Clinically relevant adverse reactions in < 15% of patients receiving CALQUENCE plus BR included bruising, abdominal pain, atrial fibrillation or flutter, and tumor lysis syndrome.
Previously Treated Mantle Cell Lymphoma ACE-LY-004 The safety data described in this section reflect exposure to CALQUENCE (100 mg approximately every 12 hours) in 124 patients with previously treated MCL in Trial LY-004. The most common adverse reactions (≥ 20%) of any grade were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea.
Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Tables 7 and 8 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE. Table 7: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004 6 - Per NCI CTCAE version 4.03. a Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’. b Rash: Includes all terms containing ‘rash’. c Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’.
Table 8: Hematologic Adverse Reactions Reported in ≥ *Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions. Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients. Chronic Lymphocytic Leukemia The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without obinutuzumab) in 511 patients with CLL from two randomized controlled clinical trials.
The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea. ELEVATE-TN The safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicenter, open-label, actively controlled trial in 526 patients with previously untreated CLL. Patients randomized to the CALQUENCE+G arm were treated with CALQUENCE and obinutuzumab in combination for six cycles, then with CALQUENCE as monotherapy until disease progression or unacceptable toxicity.
Patients initiated obinutuzumab on Day 1 of Cycle 2, continuing for a total of 6 cycles. Patient randomized to CALQUENCE monotherapy received CALQUENCE approximately every 12 hours until disease progression or unacceptable toxicity. Eighty-five percent of patients in the CALQUENCE+G arm received at least 6 cycles of obinutuzumab.
In the CALQUENCE+G and CALQUENCE monotherapy arms, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. In the CALQUENCE+G arm, adverse reactions led to treatment discontinuation in 11% of patients and a dose reduction of CALQUENCE in 7% of patients. In the CALQUENCE monotherapy arm, adverse reactions led to discontinuation in 10% and dose reduction in 4% of patients.
Tables 9 and 10 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial. Table 9: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN) 6 0 *Per NCI CTCAE version 4.03. Includes any adverse reactions involving infection or febrile neutropenia. Includes 3 fatal cases in the CALQUENCE plus obinutuzumab arm, 3 fatal cases in the CALQUENCE monotherapy arm and 1 fatal case in the obinutuzumab plus chlorambucil arm. § Includes upper respiratory tract infection, nasopharyngitis and sinusitis. a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. b Derived from adverse reaction and laboratory data. c Includes neutropenia, neutrophil count decreased, and related laboratory data. d Includes anemia, red blood cell count decreased, and related laboratory data. e Includes thrombocytopenia, platelet count decreased, and related laboratory data. f Includes lymphocytosis, lymphocyte count increased, and related laboratory data. g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. h Includes asthenia, fatigue, and lethargy. i Includes bruise, contusion, and ecchymosis. j Includes rash, dermatitis, and other related terms. k Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis. Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE (CALQUENCE in combination with obinutuzumab and monotherapy) included: • Neoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%) • Cardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%) • Infection: herpesvirus infection (6%) Table: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN) % of patients in the CALQUENCE combination arm and monotherapy arm, respectively.
ASCEND The safety of CALQUENCE in patients with relapsed or refractory CLL was evaluated in a randomized, open-label study (ASCEND). The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times ULN, total bilirubin ≤ 1.5 times ULN, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded patients having an absolute neutrophil count < 500/µL, platelet count < 30,000/µL, prothrombin time or activated partial thromboplastin time > 2 times ULN, significant cardiovascular disease, or a requirement for strong CYP3A inhibitors or inducers.
Patients were allowed to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonist. In the CALQUENCE arm, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%).
Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection. In recipients of CALQUENCE, permanent discontinuation due to an adverse reaction occurred in 10% of patients, most frequently due to second primary malignancies followed by infection. Adverse reactions led to dosage interruptions of CALQUENCE in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and dose reduction in 3.9% of patients.
Selected adverse reactions are described in Table 11 and non-hematologic laboratory abnormalities are described in Table 12. Eighty-three percent of patients completed 6 cycles of bendamustine and rituximab product. AMPLIFY The safety of CALQUENCE in patients with previously untreated CLL was evaluated in a randomized, multicenter, open-label study (AMPLIFY), in which 291 patients received CALQUENCE plus venetoclax (AV), and 259 patients received Investigator’s choice of FCR/BR (fludarabine plus cyclophosphamide plus rituximab or bendamustine plus rituximab).
Among patients who received AV, 96% were exposed for 6 months or longer and 91% were exposed for greater than one year. Serious adverse reactions occurred in 25% of patients receiving AV. Fatal adverse events occurred in 3.4% of patients.
The most common fatal adverse events included COVID-19 and COVID-19 pneumonia. Treatment discontinuation of CALQUENCE due to adverse reactions occurred in 8% of patients receiving AV. The most common adverse reaction (≥ 2%) leading to treatment discontinuation was COVID-19 pneumonia (2.1%).
Dose reduction of CALQUENCE occurred in 6% of patients. Neutropenia was the only adverse reaction leading to dose reduction that occurred in ≥ 1% of patients. Table 13 and Table 14 summarize select adverse reactions and laboratory abnormalities observed in patients treated in AMPLIFY.
Table 13: Adverse Reactions* (≥ 15% Any Grade) in Patients with Previously Untreated CLL Who Received CALQUENCE plus Venetoclax in AMPLIFY Clinically relevant adverse reactions in < 15% of patients receiving CALQUENCE plus Venetoclax included upper respiratory tract infections, lower respiratory tract infection, arthralgia, pneumonia, hemorrhage, dizziness, constipation, vomiting, second primary malignancy and hypertension. Table 14: Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in in Patients with Previously Untreated CLL Who Received CALQUENCE plus Venetoclax in AMPLIFY % of patients treated with CALQUENCE plus Venetoclax include absolute neutrophil count decreased (15%).
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of CALQUENCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Cardiac disorders: ventricular arrhythmias • Hepatobiliary disorders: drug induced liver injury
| Body System Adverse Reactions* | CALQUENCE plus BR N = 297 | Placebo plus BR N = 297 | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Skin and subcutaneous tissue disorders | ||||
| Rash a | 47 | 12 | 31 | 3 |
| Infections | ||||
| COVID-19 b | 38 | 13 | 27 | 11 |
| Upper respiratory tract infection c | 30 | 0.7 | 29 | 1 |
| Pneumoniad d | 31 | 17 | 25 | 14 |
| Gastrointestinal disorders | ||||
| Diarrhea | 37 | 3 | 28 | 2.4 |
| Vomiting | 26 | 0.7 | 14 | 1 |
| Constipation | 25 | 1 | 25 | 0.3 |
| General disorders | ||||
| Fatigue | 37 | 3.7 | 32 | 4.4 |
| Pyrexia | 29 | 2.4 | 24 | 1.3 |
| Edema | 20 | 1.3 | 19 | 0 |
| Nervous system disorders | ||||
| Headache | 31 | 1.7 | 14 | 0.7 |
| Dizziness | 18 | 1 | 17 | 0.3 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 27 | 0 | 20 | 0.3 |
| Dyspnea | 17 | 1 | 11 | 2.7 |
| Neoplasms | ||||
| Secondary primary malignancy e | 19 | 7 | 15 | 7 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 18 | 0.7 | 16 | 1 |
| Vascular disorders | ||||
| Hemorrhage f | 20 | 1.7 | 11 | 3 |
| *Excludes laboratory terms. a Includes rash, dermatitis, and other related terms. b Includes the following fatal adverse reactions: n=24 for COVID-19. c Includes upper respiratory tract infection, sinusitis, pharyngitis, and related terms. d Includes pneumonia, terms containing pneumonia, and related infections. COVID-19 pneumonia is represented under both Pneumonia and COVID-19. e Includes terms related to malignant neoplasms including cutaneous neoplasms. f Includes all terms containing hematoma or hemorrhage and related terms indicative of bleeding. | ||||
| Laboratory Abnormality | CALQUENCE plus BR a | Placebo plus BR a | ||
|---|---|---|---|---|
| All grade (%) | Grade 3 or 4 (%) | All grade (%) | Grade 3 or 4 (%) | |
| Hematologic Abnormalities | ||||
| Lymphocytes decreased | 98 | 87 | 97 | 89 |
| Hemoglobin decreased | 80 | 11 | 65 | 11 |
| Neutrophils decreased | 76 | 56 | 77 | 51 |
| Platelets decreased | 69 | 18 | 60 | 16 |
| Chemistry Abnormalities | ||||
| AST increased | 53 | 5 | 50 | 3.4 |
| Uric acid increased | 45 | 45 | 40 | 40 |
| ALT increased | 44 | 7 | 41 | 2.4 |
| Potassium increased | 40 | 2 | 38 | 2.7 |
| Creatinine increased | 37 | 3 | 28 | 2.4 |
| Phosphate decreased | 36 | 4.4 | 30 | 4.7 |
| Potassium decreased | 29 | 7 | 23 | 6 |
| Bilirubin increased | 19 | 2 | 12 | 2 |
| a The denominator used to calculate the rate varied between 296 and 297 based on the number of patients with a baseline value and at least one post-treatment value. | ||||
| Body System Adverse Reactions* | CALQUENCE Monotherapy N=124 | |
|---|---|---|
| All Grades (%) | Grade ≥ 3 (%) | |
| Nervous system disorders | ||
| Headache | 39 | 1.6 |
| Gastrointestinal disorders | ||
| Diarrhea | 31 | 3.2 |
| Nausea | 19 | 0.8 |
| Abdominal pain | 15 | 1.6 |
| Constipation | 15 | - |
| Vomiting | 13 | 1.6 |
| General disorders | ||
| Fatigue | 28 | 0.8 |
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | 21 | 0.8 |
| Skin and subcutaneous tissue disorders | ||
| Bruising a | 21 | - |
| Rash b | 18 | 0.8 |
| Vascular disorders | ||
| Hemorrhage c | 8 | 0.8 |
| Respiratory, thoracic and mediastinal disorders | ||
| Epistaxis | 6 | - |
| Hematologic Adverse Reactions | CALQUENCE Monotherapy N=124 | |
|---|---|---|
| All Grades (%) | Grade ≥ 3 (%) | |
| Hemoglobin decreased | 46 | 10 |
| Platelets decreased | 44 | 12 |
| Neutrophils decreased | 36 | 15 |
| Body System Adverse Reaction | CALQUENCE plus Obinutuzumab N=178 | CALQUENCE Monotherapy N=179 | Obinutuzumab plus Chlorambucil N=169 | |||
|---|---|---|---|---|---|---|
| All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Infections | ||||||
| Infection | 69 | 22 | 65 | 14 | 46 | 13 |
| Upper respiratory tract infection § | 39 | 2.8 | 35 | 0 | 17 | 1.2 |
| Lower respiratory tract infection a | 24 | 8 | 18 | 4.5 | 7 | 1.8 |
| Urinary tract infection | 15 | 1.7 | 15 | 2.8 | 5 | 0.6 |
| Blood and lymphatic system disorders b | ||||||
| Neutropenia c | 53 | 37 | 23 | 13 | 78 | 50 |
| Anemia d | 52 | 12 | 53 | 10 | 54 | 14 |
| Thrombocytopenia e | 51 | 12 | 32 | 3.4 | 61 | 16 |
| Lymphocytosis f | 12 | 11 | 16 | 15 | 0.6 | 0.6 |
| Nervous system disorders | ||||||
| Headache | 40 | 1.1 | 39 | 1.1 | 12 | 0 |
| Dizziness | 20 | 0 | 12 | 0 | 7 | 0 |
| Gastrointestinal disorders | ||||||
| Diarrhea | 39 | 4.5 | 35 | 0.6 | 21 | 1.8 |
| Nausea | 20 | 0 | 22 | 0 | 31 | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal pain g | 37 | 2.2 | 32 | 1.1 | 16 | 2.4 |
| Arthralgia | 22 | 1.1 | 16 | 0.6 | 4.7 | 1.2 |
| General disorders and administration site conditions | ||||||
| Fatigue h | 34 | 2.2 | 23 | 1.1 | 24 | 1.2 |
| Skin and subcutaneous tissue disorders | ||||||
| Bruising i | 31 | 0 | 21 | 0 | 5 | 0 |
| Rash j | 26 | 2.2 | 25 | 0.6 | 9 | 0.6 |
| Vascular disorders | ||||||
| Hemorrhagek | 20 | 1.7 | 20 | 1.7 | 6 | 0 |
| Laboratory Abnormality Per NCI CTCAE version 4.03 Excludes electrolytes | CALQUENCE plus Obinutuzumab N=178 | CALQUENCE Monotherapy N=179 | Obinutuzumab plus Chlorambucil N=169 | |||
|---|---|---|---|---|---|---|
| All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Uric acid increase | 29 | 29 | 22 | 22 | 37 | 37 |
| ALT increase | 30 | 7 | 20 | 1.1 | 36 | 6 |
| AST increase | 38 | 5 | 17 | 0.6 | 60 | 8 |
| Bilirubin increase | 13 | 0.6 | 15 | 0.6 | 11 | 0.6 |
| Body System Adverse Reaction | CALQUENCE N=154 | Idelalisib plus Rituximab Product N=118 | Bendamustine plus Rituximab Product N=35 | |||
|---|---|---|---|---|---|---|
| All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Infections | ||||||
| Infection | 56 | 15 | 65 | 28 | 49 | 11 |
| Upper respiratory tract infection § | 29 | 1.9 | 26 | 3.4 | 17 | 2.9 |
| Lower respiratory tract infection a | 23 | 6 | 26 | 15 | 14 | 6 |
| Blood and lymphatic system disorders b | ||||||
| Neutropenia c | 48 | 23 | 79 | 53 | 80 | 40 |
| Anemia d | 47 | 15 | 45 | 8 | 57 | 17 |
| Thrombocytopenia e | 33 | 6 | 41 | 13 | 54 | 6 |
| Lymphocytosis f | 26 | 19 | 23 | 18 | 2.9 | 2.9 |
| Nervous system disorders | ||||||
| Headache | 22 | 0.6 | 6 | 0 | 0 | 0 |
| Gastrointestinal disorders | ||||||
| Diarrhea g | 18 | 1.3 | 49 | 25 | 14 | 0 |
| Vascular disorders | ||||||
| Hemorrhage h | 16 | 1.3 | 5 | 1.7 | 6 | 2.9 |
| General disorders | ||||||
| Fatigue i | 15 | 1.9 | 13 | 0.8 | 31 | 6 |
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal pain j | 15 | 1.3 | 15 | 1.7 | 2.9 | 0 |
| Laboratory Abnormality Excludes electrolytes | CALQUENCE N=154 | Idelalisib plus Rituximab Product N=118 | Bendamustine plus Rituximab Product N=35 | |||
|---|---|---|---|---|---|---|
| All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Uric acid increase | 15 | 15 | 11 | 11 | 23 | 23 |
| ALT increase | 15 | 1.9 | 59 | 23 | 26 | 2.9 |
| AST increase | 13 | 0.6 | 48 | 13 | 31 | 2.9 |
| Bilirubin increase | 13 | 1.3 | 16 | 1.7 | 26 | 11 |
| Per NCI CTCAE version 5 | ||||||
| Body System Adverse Reactions | CALQUENCE plus Venetoclax N = 291 | Investigator’s choice of FCR or BR N = 259 | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Nervous system disorders | ||||
| Headache | 35 | 1.4 | 8 | 0.4 |
| Gastrointestinal disorders | ||||
| Diarrhea | 33 | 1.7 | 11 | 0.4 |
| Nausea | 15 | 0 | 36 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain a | 25 | 0.7 | 14 | 0.8 |
| Infections | ||||
| COVID-19 | 21 | 6 | 3.9 | 1.5 |
| General disorders | ||||
| Fatigue b | 18 | 0.3 | 17 | 1.5 |
| Skin and subcutaneous tissue disorders | ||||
| Bruising c | 17 | 0 | 1.5 | 0 |
| Rash d | 16 | 1 | 16 | 1.5 |
| *Excludes laboratory terms. a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain, non-cardiac chest pain and pain in jaw. b Includes fatigue and asthenia. c Includes increased tendency to bruise, contusion, and ecchymosis. d Includes rash, dermatitis, and other related terms. | ||||
| Laboratory Abnormality | CALQUENCE plus Venetoclax a | Investigator’s choice of FCR or BR a | ||
|---|---|---|---|---|
| All grade (%) | Grade 3 or 4 (%) | All grade (%) | Grade 3 or 4 (%) | |
| Hematologic Abnormalities | ||||
| Neutrophils decreased | 78 | 38 | 80 | 53 |
| Lymphocytes decreased | 56 | 12 | 92 | 73 |
| Platelets decreased | 43 | 5 | 59 | 15 |
| Hemoglobin decreased | 35 | 7 | 56 | 8 |
| Chemistry Abnormalities | ||||
| Glucose increased | 74 | 0 | 84 | 0 |
| Calcium decreased | 30 | 0.7 | 25 | 2.3 |
| ALT increased | 26 | 3.1 | 28 | 1.6 |
| Urate increased | 25 | 25 | 23 | 23 |
| LDH increased | 24 | 0 | 40 | 0 |
| Potassium increased | 22 | 2.4 | 12 | 3.1 |
| AST increased | 22 | 1.4 | 28 | 1.6 |
| ALP increased | 20 | 0 | 15 | 0 |
| Glucose decreased | 20 | 0.3 | 5 | 0 |
| Creatinine increased | 19 | 0.3 | 12 | 0.8 |
| Sodium increased | 15 | 0.3 | 9 | 0.4 |
| a The denominator used to calculate the rate varied between 256 and 290 based on the number of patients with a baseline value and at least one post-treatment value. | ||||
Warnings & Cautions for Calquence
Serious and Opportunistic Infections Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML).
Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly. In an additional cohort of patients receiving CALQUENCE in combination with venetoclax with obinutuzumab (AVO) (an unapproved regimen for previously untreated CLL/SLL in AMPLIFY), serious or Grade 3 or higher infections occurred in 25% receiving AVO compared to 14% in patients receiving AV.
Fatal infections occurred in 6% receiving AVO compared to 3.1% of patients receiving AV, most commonly due to COVID-19. The safety and effectiveness of AVO has not been established in patients with previously untreated CLL/SLL.
Hemorrhage Fatal and serious hemorrhagic events have occurred in patients treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients.
Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE.
Monitor patients for signs of bleeding. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.
Second Primary Malignancies
Second primary malignancies, including skin cancers and other solid tumors, occurred in 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients.
Monitor patients for the development of second cancers and advise protection from sun exposure.
Cardiac Arrhythmias Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection.
Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.
Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE. Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity.
If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.
Drug Interactions with Calquence
Effect of Other Drugs on CALQUENCE Strong CYP3A Inhibitors Clinical Effect Co-administration of CALQUENCE with a strong CYP3A inhibitor increased acalabrutinib plasma concentrations. Prevention or Management Avoid co-administration of CALQUENCE with strong CYP3A inhibitors. Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE.
Moderate CYP3A Inhibitors Clinical Effect Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentration. Prevention or Management Reduce the dosage of CALQUENCE when co-administered with a moderate CYP3A inhibitor. Strong CYP3A Inducers Clinical Effect Co-administration of CALQUENCE with a strong CYP3A inducer decreased acalabrutinib plasma concentration.
If co-administration is unavoidable, increase the dosage of CALQUENCE.
| Strong CYP3A Inhibitors | |
| Clinical Effect | Co-administration of CALQUENCE with a strong CYP3A inhibitor increased acalabrutinib plasma concentrations [see Clinical Pharmacology (12.3) ]. Increased acalabrutinib concentrations may result in increased toxicity. |
| Prevention or Management | Avoid co-administration of CALQUENCE with strong CYP3A inhibitors. Alternatively, if the inhibitor will be used short-term, interrupt CALQUENCE [see Dosage and Administration (2.2) ]. |
| Moderate CYP3A Inhibitors | |
| Clinical Effect | Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentration [see Clinical Pharmacology (12.3) ]. Increased acalabrutinib concentrations may result in increased toxicity. |
| Prevention or Management | Reduce the dosage of CALQUENCE when co-administered with a moderate CYP3A inhibitor [see Dosage and Administration (2.2) ]. |
| Strong CYP3A Inducers | |
| Clinical Effect | Co-administration of CALQUENCE with a strong CYP3A inducer decreased acalabrutinib plasma concentration [see Clinical Pharmacology (12.3) ]. Decreased acalabrutinib concentrations may reduce CALQUENCE activity. |
| Prevention or Management | Avoid co-administration of CALQUENCE with strong CYP3A inducers. If co-administration is unavoidable, increase the dosage of CALQUENCE [see Dosage and Administration (2.2) ]. |
Pregnancy Safety for Calquence
Pregnancy Risk Summary Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of acalabrutinib to animals during organogenesis resulted in dystocia in rats and reduced fetal growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg approximately every 12 hours ( see Data ).
Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day 17. No effects on embryo-fetal development and survival were observed.
The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma. In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses ≥ 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed skeletal ossification.
In a pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult labor) and mortality of offspring were observed at doses ≥ 100 mg/kg/day.
Pediatric Use of Calquence
Pediatric Use The safety and efficacy of CALQUENCE in pediatric patients have not been established.
Clinical Studies of Calquence
Previously Untreated Mantle Cell Lymphoma
DOCVARIABLE vault_nd_4d1e0c80-2ff6-409f-bee7-897264eadbff \ MERGEFORMAT ECHO The efficacy of CALQUENCE in patients with previously untreated MCL was evaluated in a randomized, double blind, placebo controlled, multicenter study (ECHO; NCT02972840). The study enrolled 598 patients who were ≥ 65 years of age and who had no intention for transplant. The study excluded patients with total bilirubin > 1.5 × upper limit of normal (ULN), AST or ALT > 2.5 × ULN, or estimated creatinine clearance of ≤ 50 mL/min.
Patients were randomized in a 1:1 ratio to receive CALQUENCE plus bendamustine and rituximab (CALQUENCE plus BR) or placebo plus BR. Dosing for both arms was administered in 28-day cycles as follows: • CALQUENCE plus BR was administered for a maximum of 6 treatment cycles. CALQUENCE 100 mg orally was administered twice daily starting on Cycle 1 Day 1.
After discontinuation of rituximab, patients continued CALQUENCE monotherapy at 100 mg orally twice daily until disease progression or unacceptable toxicity. Patients on the control arm received the same regimen but placebo in lieu of CALQUENCE. Crossover to CALQUENCE monotherapy was permitted for patients in the placebo plus BR arm at disease progression.
In total, 80% had classic histology of MCL, 7.7% had blastoid MCL, and 5.5% had pleomorphic MCL. The simplified MIPI (Mantle Cell Lymphoma International Prognostic Index) score was low in 33%, intermediate in 43%, and high in 24% of patients. A total of 38% of patients had tumor bulk ≥ 5 cm and 86% had Ann Arbor stage IV disease.
The major efficacy outcome was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) using the Lugano Classification. Efficacy results are presented in Table 15. The Kaplan-Meier curves for PFS are shown in Figure 1.
At this prespecified interim analysis, the median follow-up for PFS was 49.8 months in both arms. Table 15. Efficacy Results in Patients with Previously Untreated MCL in ECHO a Stratified by randomization stratification factors: Geographic Regions (North American, Western Europe, Other) and simplified MIPI Score (Low risk, Intermediate risk, High Risk ). b Estimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI). c Estimated based on stratified log-rank test for p-value, with an alpha level of 0.039 derived by the O’Brien-Fleming method.
Figure 1. Kaplan-Meier Curve of IRC-Assessed PFS in Patients with Previously Untreated MCL in ECHO At the time of the PFS analysis, the median overall survival had not been reached in either arm with a total of 203 deaths: 97 (32%) patients in the CALQUENCE plus BR arm and 106 (35%) patients in the placebo plus BR arm had died. Figure_1
Previously Treated Mantle Cell Lymphoma ACE-LY-004
The efficacy of CALQUENCE was based upon Trial LY-004 titled “An Open-label, Phase 2 Study of ACP-196 in Subjects with Mantle Cell Lymphoma” (NCT02213926). Trial LY-004 enrolled a total of 124 patients with MCL who had received at least one prior therapy. At baseline, 93% of patients had an ECOG performance status of 0 or 1.
Patients who received prior treatment with BTK inhibitors were excluded. The most common prior regimens were CHOP-based (52%) and ARA-C (34%). The simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients.
CALQUENCE was administered orally at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. The major efficacy outcome of Trial LY-004 was overall response rate and the median follow-up was 15.2 months.
Table 16: Efficacy Results in Patients with MCL in Trial LY-004 Investigator Assessed N=124 Independent Review Committee (IRC) Assessed N=124 Overall Response Rate (ORR) Per 2014 Lugano Classification. The median time to best response was 1.9 months. Lymphocytosis Upon initiation of CALQUENCE, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased ≥ 50% from baseline and a post-baseline assessment ≥ 5 x 109/L) in 31.5% of patients in Trial LY-004.
The median time to onset of lymphocytosis was 1.1 weeks, and the median duration of lymphocytosis was 6.7 weeks.
Chronic Lymphocytic Leukemia
The efficacy of CALQUENCE in patients with CLL was demonstrated in two randomized, controlled trials. The indication for CALQUENCE includes patients with SLL because it is the same disease. ELEVATE-TN The efficacy of CALQUENCE was evaluated in the ELEVATE-TN trial, a randomized, multicenter, open-label, actively controlled, 3 arm trial of CALQUENCE in combination with obinutuzumab, CALQUENCE monotherapy, and obinutuzumab in combination with chlorambucil in 535 patients with previously untreated chronic lymphocytic leukemia (NCT02475681).
The trial also required hepatic transaminases ≤ 3 times upper limit of normal (ULN) and total bilirubin ≤ 1.5 times ULN, and excluded patients with Richter’s transformation. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Each cycle was 28 days. • CALQUENCE monotherapy: CALQUENCE 100 mg was administered approximately every 12 hours until disease progression or unacceptable toxicity. • Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles.
Each cycle was 28 days. Randomization was stratified by 17p deletion mutation status, ECOG performance status (0 or 1 versus 2), and geographic region. Baseline demographic and disease characteristics were similar between treatment arms.
Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up was 28.3 months (range: 0.0 to 40.8 months). Efficacy results are presented in Table 17.
Table 17. Efficacy Results per IRC in Patients with CLL ‒ ITT population (ELEVATE-TN) Figure 2: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ELEVATE-TN With a median follow-up of 28.3 months, median overall survival was not reached in any arm, with fewer than 10% of patients experiencing an event. ASCEND The efficacy of CALQUENCE in patients with relapsed or refractory CLL was based upon a multicenter, randomized, open-label trial (ASCEND; NCT02970318).
The trial enrolled 310 patients with relapsed or refractory CLL after at least 1 prior systemic therapy. The trial excluded patients with transformed disease, prolymphocytic leukemia, or previous treatment with venetoclax, a Bruton tyrosine kinase inhibitor, or a phosphoinositide-3 kinase inhibitor. Efficacy was based on PFS as assessed by an IRC, with a median follow-up of 16.1 months (range 0.03 to 22.4 months).
Efficacy results are presented in Table 18. The Kaplan-Meier curve for PFS is shown in Figure 3. There was no statistically significant difference in overall response rates between the two treatment arms.
Table 18: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL – ITT Population (ASCEND) Figure 3: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL in ASCEND With a median follow-up of 16.1 months, median overall survival was not reached in either arm, with fewer than 11% of patients experiencing an event. AMPLIFY The efficacy of CALQUENCE in combination with venetoclax in previously untreated CLL patients was evaluated in AMPLIFY, a randomized, multi-center, open-label study (NCT03836261). The study included patients previously untreated for CLL without del(17p) or TP53 mutation that were 18 years of age and older.
Venetoclax was administered for a total of 12 cycles. Each cycle was 28 days. • An additional investigational combination regimen. Patients were stratified by age (> 65 years or ≤ 65), IGHV mutational status (mutated versus unmutated), Rai stage (high risk versus non-high risk) and geographic region (North America and Europe versus other).
The major efficacy outcome was IRC-assessed PFS of AV arm versus Investigator’s choice arm (FCR/BR). The median duration of PFS follow-up was 42.6 months. Efficacy results are presented in Table 19.
Table 19. Efficacy Results per IRC in Patients with previously untreated CLL ‒ ITT population (AMPLIFY) Figure 4: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with previously untreated CLL in AMPLIFY With a median follow-up of 41.0 months, a total of 60 death events were reported; 18 (6%) in the AV arm and 42 (14%) in the FCR/BR arm. figure_2 figure_3 figure_4
| Outcomes per IRC | CALQUENCE plus BR N= 299 | Placebo plus BR N= 299 |
|---|---|---|
| Progression-Free Survival a | ||
| Median (95% CI), months | 66.4 (55.1, NE) | 49.6 (36.0, 64.1) |
| HR b (95% CI) | 0.73 (0.57, 0.94) | |
| P-value c | 0.016 | |
| Overall Response Rate (ORR) (CR + PR) | ||
| ORR n (%) | 272 (91) | 263 (88) |
| 95% CI | 87, 94 | 84, 91 |
| CR n (%) | 199 (67) | 160 (54) |
| PR n (%) | 73 (24) | 103 (34) |
| p-value | 0.220 | |
| HR = hazard ratio, CR = complete response, PR = partial response, NE – not evaluable | ||
| Investigator Assessed N=124 | Independent Review Committee (IRC) Assessed N=124 | |
|---|---|---|
| Overall Response Rate (ORR) Per 2014 Lugano Classification. | ||
| ORR (%) [95% CI] | 81 [73, 87] | 80 [72, 87] |
| Complete Response (%) [95% CI] | 40 [31, 49] | 40 [31, 49] |
| Partial Response (%) [95% CI] | 41 [32, 50] | 40 [32, 50] |
| Duration of Response (DoR) | ||
| Median DoR in months [range] | NE [1+ to 20+] | NE [0+ to 20+] |
| CI= Confidence Interval; NE=Not Estimable; + indicates censored observations. | ||
| CALQUENCE plus Obinutuzumab N=179 | CALQUENCE Monotherapy N=179 | Obinutuzumab plus Chlorambucil N=177 | |
|---|---|---|---|
| Progression-Free Survival Per 2008 International Workshop on CLL (IWCLL) criteria. | |||
| Number of events (%) | 14 (8) | 26 (15) | 93 (53) |
| PD, n (%) | 9 (5) | 20 (11) | 82 (46) |
| Death events, n (%) | 5 (3) | 6 (3) | 11 (6) |
| Median (95% CI), months Kaplan-Meier estimate. | NE | NE (34, NE) | 22.6 (20, 28) |
| HR Based on a stratified Cox-Proportional-Hazards model. Both hazard ratios are compared with the obinutuzumab and chlorambucil arm. (95% CI) | 0.10 (0.06, 0.17) | 0.20 (0.13, 0.30) | - |
| p-value Based on a stratified log-rank test, with an alpha level of 0.012 derived from alpha spending function by the O’Brien-Fleming method. | < 0.0001 | < 0.0001 | - |
| Overall Response Rate (CR + CRi + nPR + PR) | |||
| ORR, n (%) | 168 (94) | 153 (86) | 139 (79) |
| (95% CI) | (89, 97) | (80, 90) | (72, 84) |
| p-value Based on a stratified Cochran–Mantel–Haenszel test, for the comparison with the obinutuzumab and chlorambucil arm. | < 0.0001 | 0.0763 | - |
| CR, n (%) | 23 (13) | 1 (1) | 8 (5) |
| CRi, n (%) | 1 (1) | 0 | 0 |
| nPR, n (%) | 1 (1) | 2 (1) | 3 (2) |
| PR, n (%) | 143 (80) | 150 (84) | 128 (72) |
| ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response. | |||
| CALQUENCE Monotherapy N=155 | Investigator’s Choice of Idelalisib + Rituximab Product or Bendamustine + Rituximab Product N=155 | |
|---|---|---|
| Progression-Free Survival Per 2008 IWCLL criteria. | ||
| Number of events, n (%) | 27 (17) | 68 (44) |
| Disease progression, n | 19 | 59 |
| Death, n | 8 | 9 |
| Median (95% CI), months Kaplan-Meier estimate. | NE (NE, NE) | 16.5 (14.0, 17.1) |
| HR (95% CI) Based on a stratified Cox-Proportional-Hazards model. | 0.31 (0.20, 0.49) | |
| P-value Based on a stratified Log-rank test. The pre-specified type I error rate (α) for this interim analysis is 0.012 derived from a Lan-DeMets alpha spending function with O’Brien-Fleming boundary. | < 0.0001 | |
| Overall Response Rate (CR + CRi + nPR + PR) Through a hierarchical testing procedure, the difference in ORR was not statistically significant, based on a Cochran-Mantel-Haenszel test with adjustment for randomization stratification factors. | ||
| ORR, n (%) | 126 (81) | 117 (75) |
| (95% CI) | (74, 87) | (68, 82) |
| CR, n (%) | 0 | 2 (1) |
| CRi, n (%) | 0 | 0 |
| nPR, n (%) | 0 | 0 |
| PR, n (%) | 126 (81) | 115 (74) |
| ITT=intent-to-treat; CI=confidence interval; HR=hazard ratio; NE=not estimable; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response | ||
| CALQUENCE plus venetoclax N=291 | FCR/BR b N=290 | |
|---|---|---|
| Progression-free survival a | ||
| Number of events (%) | 89 (31) | 95 (33) |
| PD, n (%) | 77 (26) | 66 (23) |
| Death events (%) | 12 (4) | 29 (10) |
| Median (95% CI), months | NE (51.1, NE) | 47.6 (43.3, NE) |
| HR c (95% CI) | 0.65 (0.49, 0.87) | |
| P-value d | 0.0038 | |
| Overall Response Rate (CR, CRi, nPR, PR) e | ||
| ORR n (%) | 270 (93) | 218 (75) |
| (95% CI) | (89, 95) | (70, 80) |
| CR | 26 (9) | 15 (5) |
| CRi, n (%) | 0 | 1 (0.3) |
| nPR, n (%) | 1 (0.3) | 1 (0.3) |
| PR n (%) | 243 (84) | 201 (69) |
| NE= Not estimable; CR = complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response a Per IRC assessment. b Approximately 50% of patients were treated with FCR and 50% were treated with BR per investigator's choice. c Based on stratified Cox-Proportional-Hazards model. d Based on a stratified Log-rank test. The pre-specified type I error rate (α) for this interim analysis is 0.0469 derived from a Lan-DeMets alpha spending function with O’Brien-Fleming boundary. e Per iwCLL 2018 criteria. | ||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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