| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic lymphocytic leukemia (CLL) |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the blood and bone marrow |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008977 |
| E.1.2 | Term | Chronic lymphocytic leukemia recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to assess the efficacy of venetoclax (Ven) in combination with obinutuzumab (G), (VenG), in subjects with CLL who previously received venetoclax + anti-CD20 antibody ± X as a fixed duration therapy, achieved a response, and subsequently progressed no sooner than 24 months after completing 1L treatment (Cohort 1), based on overall response rate (ORR) after completion of the combination phase of the study. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary efficacy objective is to evaluate the efficacy of treatment with VenG in Cohort 1 with respect to specified secondary endpoints. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Adult individuals, at least 18 years old.
•Subjects 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.
•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
• Previously completed venetoclax + anti-CD20 antibody ± X (where X is any additional drug) as first line fixed duration therapy and achieved documented response, defined as CR, CRi, PR, or nPR.
•Patients who will not receive approved second-line therapies as assessed by the investigator and patient preference may be eligible for the study.
•a) For Cohort 1: More than 24 months between the last dose of venetoclax and progression re-quiring treatment after completion of 1L venetoclax + anti-CD20 antibody ± X treatment; b) for Cohort 2: 12- 24 months be-tween the last dose of venetoclax and progression requiring treatment after completion of 1L venetoclax + anti-CD20 antibody ± X treatment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
• Pregnancy testing in all females subjects of child-bearing potential; a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug; more frequent testing is acceptable if required per local regulation.
•Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control, that is effective from Study Day 1 through at least 30 days after the last dose of venetoclax and at least 18 months after the last dose of obinutuzumab. Female subjects of non-childbearing potential do not need to use birth control.
•Male subject, who is sexually active with female partner(s) of childbearing potential, he must agree, from Study Day 1 for at least 3 months after the last dose of obinutuzumab and/or ve-netoclax, to practice the protocol-specified contraception. In addition, his female partner(s) of childbearing potential must use at least one of the contraceptive measures as defined.
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| E.4 | Principal exclusion criteria |
•Subject has not received an intervening treatment for CLL after completing previous treatment with venetoclax + anti-CD20 antibody ±X.
•Subject has no contraindication for all available uric acid reducing agents.
•Subject has not discontinued prior venetoclax + anti-CD20 antibody ± X treatment due to PD during treatment.
•No active or uncontrolled autoimmune hemolytic anemia or immune thrombocytope-nic purpura.
•No 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.
•No history of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same class.
•No positive test results for, or suspicion of, hepatitis B virus infection (HBV) infection (defined as positive hepatitis B surface antibody [HBsAg] serology), based on site standard practices prior to anti-CD20 antibody infusion and obinutuzumab prescribing information.3 Testing should be conducted prior to initiation of obinutuzumab per site standard of care and obinutuzumab prescribing information.
•For subjects who show evidence of hepatitis B infection (HBsAg positive [regardless of anti-body status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.
•Subjects may be included if HBV DNA is undetectable, provided that they are willing to under-go monthly DNA testing, during and for several months following treatment with obinutuzumab. Subjects who have protective titers of hepatitis B surface antibody (HBsAb) af-ter vaccination or prior but cured hepatitis B are eligible.
•No positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing), based on site standard practices prior to anti-CD20 antibody infusion and obinutuzumab prescribing information.3
•No known active SARS-CoV-2 infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test or 2 negative antigen test results at least 24 hours apart. Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/recommendations. In addition, if the site considers the subject currently at risk for developing SARS-CoV-2 infection, then the subject should either be tested or advised to come back for study screening after 14 days.
• No conditions that could interfere with drug absorption including but not limited to short bowel syndrome.
•No significant cardiovascular issues, such as uncontrolled or symptomatic arrhythmias, myocardial infarction within 6 months of
study treatment, any class III or IV cardiac disease per New York Heart Association.
•No known positive test result(s) for human immunodeficiency virus.
•No significant toxicity from prior treatment that has not resolved to Grade ≤ 1. Exceptions (e.g., alopecia) are allowed per Investigator
discretion.
•Subject must not have used known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers from 7 days prior to venetoclax initiation through dose ramp-up, nor other prohibited drugs and food products within 3 days prior to first dose of study drug (see Section 5.3).
•Subject must not have received any live vaccine within 4 weeks prior to the first dose of study drug or be expected need of live vaccination during study participation including at least 4 weeks after the last dose of venetoclax and/or after B cell recovery for obinutuzumab.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the overall response of CR, CRi, nPR, or PR in Cohort 1 subjects as assessed by the Investigator at EOCT, evaluated 3 months after the EOCT with VenG (EOCT + 3, i.e., Cycle 9). Disease assessments will be based on the 2018 International Workshop for Chronic Lymphocytic Leukemia (iwCLL) criteria for tumor response.14 Overall response rate is defined as the proportion of subjects achieving a best response of CR,CRi, nPR, or PR. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints, all based on Cohort 1, are:
•Overall response of CR or CRi at EOCT (assessed at EOCT+ 3)
•Overall response of CR or CRi at end of treatment assessment (EOT, assessed at EOT + 3)
•Overall response of CR, CRi, nPR, or PR at EOT (assessed at EOT + 3)
•Time to response (TTR);
• Duration of response (DOR);
• Time to next treatment (TTNT) for CLL;
• Progression-free survival (PFS)
•Overall survival (OS);
• uMRD rate (< 10-4) at EOCT, measured in PB (assessed at EOCT+ 3);
• uMRD rate (< 10-4) at EOT, measured in PB (assessed at EOT + 3)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| United Kingdom |
| United States |
| Austria |
| Bulgaria |
| Germany |
| Italy |
| Romania |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end-of-study is defined as the date of the last subject's last visit or date of last follow-up contact, whichever is later. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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