IRB Study Number 25-036
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary
Part 1:
To evaluate the incidence of treatment-emergent laboratory TLS per Howard criteria (Appendix D) or treatment-emergent hyperkalemia (potassium > 6.0 mmol/L), both requiring clinical intervention that has been confirmed by an Independent Review Committee (IRC) assessment in previously untreated subjects with CLL achieving either a medium (any lymph node [LN] 5 cm to < 10 cm OR absolute lymphocyte count [ALC] ≥ 25 × 109/L) tumor burden with CrCl of at least 80 mL/min or low (all LN < 5 cm AND ALC < 25 × 109/L) tumor burden (regardless of CrCl level) after debulking therapy, during the venetoclax ramp-up period (5-, 6- or 7-week).
Clinical Hypothesis: Venetoclax can be safely ramped-up with minimal risk of TLS post-debulking in treatment naïve subjects with CLL with a medium tumor burden with CrCl of at least 80 mL/min or low tumor burden (regardless of CrCl level) when combined with other antineoplastic agents.
The estimand corresponding to the primary objective and endpoint is:
• The proportion of the incidence of treatment-emergent laboratory TLS per Howard criteria (Appendix D) or treatment-emergent hyperkalemia (potassium > 6.0 mmol/L), both requiring clinical intervention that has been confirmed by an IRC assessment in previously untreated subjects with CLL achieving either a medium tumor burden with CrCl of at least 80 mL/min or low tumor burden (regardless of CrCl level) after debulking therapy and who receive at least one dose of venetoclax during the venetoclax ramp-up period, regardless of treatment discontinuation.
Secondary
Part 1:
• To evaluate the incidence of treatment-emergent laboratory TLS per Howard criteria (Appendix D) or treatment-emergent hyperkalemia (potassium > 6.0 mmol/L), both requiring clinical intervention that has been confirmed by an IRC assessment in previously untreated subjects with CLL achieving either a medium tumor burden with CrCl of at least 80 mL/min or low tumor burden (regardless of CrCl level) after debulking therapy at each dose level and at each laboratory monitoring point during the ramp-up period
• To assess the incidence of the TLS-related events detailed below (overall, at each dose level and at each laboratory monitoring point during the ramp-up period) in previously untreated subjects with CLL achieving either a medium tumor burden with CrCl of at least 80 mL/min or low tumor burden (regardless of CrCl level) after debulking therapy:
• Laboratory TLS per Howard criteria (2 or more lab abnormalities [hyperkalemia (potassium > 6.0 mmol/L), hyperphosphatemia (phosphorus > 4.5 mg/dL), hypocalcemia (corrected calcium < 7.0 mg/dL or ionized calcium < 4.5 mg/dL), hyperuricemia (uric acid > 8.0 mg/dL)] present during the same 24-hour period within 3 days before the start of therapy or up to 7 days after) requiring clinical intervention that has been confirmed by an IRC assessment
• Hyperkalemia (potassium > 6.0 mmol/L) requiring clinical intervention that has been confirmed by an IRC assessment
• Laboratory TLS per Howard criteria irrespective of clinical intervention
• Hyperkalemia (potassium > 6.0 mmol/L) irrespective of clinical intervention
• Clinical TLS per Howard criteria irrespective of clinical intervention
• One of the following lab abnormalities requiring clinical intervention per Investigator:
• Hyperuricemia (uric acid > 8.0 mg/dL)
• Hyperphosphatemia (phosphorus > 4.5 mg/dL)
• Hyperkalemia (potassium > 6.0 mmol/L)
• Hypocalcemia (corrected calcium < 7.0 mg/dL or ionized calcium < 4.5 mg/dL)
• To assess AEs of TLS as reported by the Investigator during the venetoclax ramp-up period in previously untreated subjects with CLL achieving either a medium tumor burden with CrCl of at least 80 mL/min or low tumor burden (regardless of CrCl level) after debulking therapy.
• To evaluate reduction of tumor burden from baseline to after debulking in all enrolled subjects who have TLS assessments performed at both baseline and after debulking.
Inclusion Criteria
Consent
- Subjects or their legally authorized representative must voluntarily sign and date an informed consent approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific procedures. Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the Sponsor or an investigator are not eligible.
Demographic and Laboratory Assessments
Individuals at least 18 years old.
Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:
• Serum alanine transaminase (ALT), serum aspartate transaminase (AST), and total bilirubin ≤ 2 × upper limit of normal (ULN), unless directly attributable to the subject's CLL;
• Creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula.
Are willing and able to comply with procedures required in this protocol.
Subjects must not be incarcerated and must be freely willing and able to provide informed consent (e.g., adults under legal protection measure [e.g., under guardianship/curatorship] or unable to express their consent and select adults under psychiatric care). Investigator's discretion should be applied.
Disease/Condition Activity
- Diagnosis of documented, previously untreated, CLL requiring treatment according to the 2018 iwCLL criteria.24 CLL must not have transformed to aggressive Non-Hodgkin's Lymphoma (NHL) (Richter's transformation or prolymphocytic leukemia) and must not have known central nervous system (CNS) involvement.
Previously untreated subjects (≥ 18 years of age) with confirmed diagnosis of SLL requiring treatment according to the 2018 iwCLL criteria will also be equally considered as CLL for eligibility, screening, treatment and evaluation.
Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as follows, unless cytopenia is due to marrow involvement of CLL:
• Absolute neutrophil count ≥ 1.0 × 109/L
• Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia attributed to CLL marrow involvement (per the discretion of the investigator), platelet count should be ≥ 10 × 109/L if there is bone marrow involvement
• Total hemoglobin ≥ 9 g/dL (without transfusion support, unless anemia is due to marrow involvement of CLL)
- Life expectancy > 6 months.
Contraception
- Pregnancy testing in female subjects of childbearing potential:
• Subjects must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at baseline prior to the first dose of study drug.
• Subjects with a borderline serum pregnancy test at Screening must have absence of clinical suspicion of pregnancy or other pathological causes of borderline results and a serum pregnancy test ≥ 3 days later to document continued lack of a positive result (unless prohibited by local requirements).
• Subjects with a urine pregnancy test at Baseline that is borderline or ambiguous must have a serum pregnancy test. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control, from Study Day 1 through at least 30 days after the last dose of venetoclax, for at least 18 months after the last dose of obinutuzumab, or at least 7 days after the last dose of acalabrutinib, whichever is longest. Female subjects of nonchildbearing potential do not need to use birth control.
Female subject who is not pregnant or breastfeeding, and is not considering becoming pregnant or donating eggs during the study or for approximately 30 days after the last dose of venetoclax, for at least 18 months after the last dose of obinutuzumab, or at least 7 days after the last dose of acalabrutinib, whichever is longest.
Male subject who is sexually active with female partner(s) of childbearing potential, must agree, from Study Day 1 through at least 30 days after the last dose of venetoclax, for at least 18 months after the last dose of obinutuzumab, or at least 7 days after the last dose of acalabrutinib, whichever is longest, to practice the protocol-specified contraception.
Male subject who is not considering fathering a child or donating sperm during the study or for at least 30 days after the last dose of venetoclax, for at least 18 months after the last dose of obinutuzumab, or at least 7 days after the last dose of acalabrutinib, whichever is longest.
Exclusion Criteria
Subject History
History of confirmed progressive multifocal leukoencephalopathy (PML).
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.
History of prior malignancy, except for conditions listed below if subjects have recovered from the acute side effects incurred as a result of previous therapy:
• Malignancies treated with curative intent and with no known active disease present for ≥ 3 years before enrollment
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Surgically adequately treated low grade, early stage localized prostate cancer without evidence of disease
Active, uncontrolled systemic infection.
History of clinically significant (per investigator's judgment) drug or alcohol abuse within the last 6 months.
Conditions that could interfere with drug absorption including but not limited to short bowel syndrome.
History of clinically significant medical conditions or any other reason that the investigator determines would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.
History of an allergic reaction or significant sensitivity to constituents of the study drugs (and their excipients) and/or other products in the same class, or to humanized or murine monoclonal antibodies or a known sensitivity to murine products.
Clinically relevant or significant ECG abnormalities, including:
• Clinically relevant or significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes),
• QT interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) > 470 msec,
• History of Mobitz II second-degree or third-degree heart block without permanent pacemaker in place.
Subjects with uncontrolled human immunodeficiency virus (HIV) infection. Subjects with controlled HIV infection (defined as viral suppression, which means having less than 200 copies of HIV per milliliter of blood25) may be included. In countries where mandatory testing by health authorities is required, HIV testing will be performed.
Subjects with known Human T-Cell Leukemia Virus 1 (HTLV-1) infection. HTLV testing is required for subjects from endemic countries (Japan, countries in the Caribbean basin, South America, Central America, sub-Saharan Africa, and Melanesia).
Known hepatitis B or C infection (HCV antibody [Ab] indicative of a current infection; and/or positive hepatitis B surface antigen [HbsAg] or detected sensitivity on hepatitis B virus [HBV]-DNA polymerase chain reaction [PCR] test for anti-hepatitis B core [HBc] Ab and/or antihepatitis B surface [HBs] Ab positivity) with the exception of subjects with an undetectable viral load within 3 months of screening. Subjects with serologic evidence of prior vaccination to HBV [i.e., HbsAg- and anti-HBsAb+] may participate.
Note: Hepatitis B or C testing is not required at Screening unless the subject is at high risk or is in an endemic region or is required per local regulations, guidelines, or institutional standards.
An individual organ/ system impairment score of 4 as assessed by the modified Cumulative Illness Rating Scale (CIRS) definition (Appendix E) limiting the ability to receive the treatment regimen of this trial.
Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening.
History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
History of stroke or intracranial hemorrhage within 180 days before first dose of study drug.
Subjects with moderate or severe hepatic impairment, e.g., Child-Pugh class B or C.
Unable to swallow acalabrutinib tablet or capsule, or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
Concomitant Medications
- Subject must not have received the following agents within 7 days prior to the first dose of study drug and must not have known medical conditions requiring chronic therapy of moderate CYP3A inducers:
• Strong CYP3A inhibitors such as posaconazole, ketoconazole, and clarithromycin
• Strong CYP3A inducers such as rifampin, carbamazepine
Subject must not have been treated with any investigational drug within 30 days or 5 halflives of the drug (whichever is longer) prior to the first dose of study drug or is currently enrolled in another clinical study or was previously enrolled in this study.
Subject must not have received any live vaccine within 4 weeks prior to the first dose of study drug or expected need of live vaccination during study participation including at least 4 weeks after the last dose of study drug or B-cell recovery (whichever is longer).
Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit (carambola) within 3 days prior to the first dose of study drug.
