| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | relapsed and refractory t(11;14) Multiple Myeloma | |
| E.1.1.1 | Medical condition in easily understood language | | cancer that forms in a type of white blood cell called a plasma cell | |
| 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 | 21.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10028228 | | E.1.2 | Term | Multiple myeloma | | E.1.2 | System Organ Class | 100000004864 | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | The primary objective of the Phase I trial part is the establishment of the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of treatment with Venetoclax in combination with Belantamab Mafodotin and with or without Dexamethasone in subjects with RRMM and t(11;14). Further, the safety profile of the combination treatment is evaluated.
In the subsequent phase IIa trial, the primary objective is the evaluation of the safety and efficacy of the established recommended dose in an expansion cohort. | |
| E.2.2 | Secondary objectives of the trial | The secondary objectives of the trial include the assessment of the
- Overall response rate (ORR)
- Minimal residual disease (MRD) negativity rate
- Progression free survival (PFS)
- Duration of response (DOR)
of the established recommended dose. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Subjects must be ≥ 18 years of age.
2. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
3. Subjects must voluntarily sign and date an informed consent form
4. Subjects must have had documented multiple myeloma requiring treatment as defined by the criteria below: Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy proven plasmacytoma at some point in their disease history requiring treatment according diagnostic criteria (IMWG updated criteria 2014, Rajkumar et al. 2014) with measurable disease at screening (serum M-protein > 500 mg/dL or urine M protein 200 mg/24h, in case of oligosecretory MM serum free light chain > 10mg/dL and abnormal kappa/lambda free light chain ratio)
5. Cytogenetics/FISH confirming t(11;14)
6. Prior treatment requirements:
Phase 1:
a. Subjects must have received at least 4 prior treatments (induction, high-dose, consolidation and maintenance is considered as one treatment line) and are refractory to at least one proteasome inhibitor, at least one immunomodulatory drug and at least one monoclonal anti CD38 antibody.
b. Subjects must have documented evidence of progressive disease during their last treatment.
Phase 2:
c. Subjects must have received at least 1 prior treatment line (induction, high-dose, consolidation and maintenance is considered as one treatment line). All patients must have received at least one proteasome inhibitor and at least one immunomodulatory agent and at least one anti CD38 monoclonal antibody.
d. Subjects must have documented evidence of progressive disease on or after the last treatment line.
Phase 1+2
e. Subjects with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met:
i. ASCT was >100 days prior to initiating study treatment, and
ii. No active bacterial, viral, or fungal infection(s) present.
7. Subjects must have adequate organ function, defined as follows:
a. Hemoglobin ≥8.0 g/dL (without transfusion of red blood cells for the past 14 days)
b. Absolute neutrophil count ≥ 1.5 x109/L (without growth factor support for the past 14 days)
c. Platelet count more or equal 75 x109/L (without growth factor or platelet stimulating agents for the past 14 days)
d. Adequate hepatic function per local laboratory reference range as follows:
i. Aspartate aminotransferase (AST) ≤ 2,5 x upper limit of normal (ULN);
ii. Alanine aminotransferase (ALT) ≤ 2.5 x ULN
iii. Total bilirubin ≤ 1.5 x ULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤ 1.5 x ULN). Isolated bilirubin ≥1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%.
e. Subjects must have adequate renal function as demonstrated by eGFR ≥30 mL/min/ 1.73 m2 as calculated by Modified Diet in Renal Disease (MDRD) formula
f. Spot urine (albumin/creatinine ratios (spot urine) <500 mg/g (56 mg/mmol)
OR Urine Dipstick Negative/trace (if 1+ only eligible if confirmed <500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void)
g. Corrected serum calcium ≤ 14 mg/dL (≤3,5 mmol/L); or free ionized calcium ˂ 6,5 mg/dL (˂1,6 mmol/L)
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
a. Is not a woman of childbearing potential (WOCBP)
OR
b. Is a WOCBP and using a contraceptive method that is highly effective and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
Non-childbearing potential must be clearly documented and be confirmed previously and is defined as follows (by other than medical reasons):
c. ≥45 years of age and has not had menses for >1 year
d. Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
e. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation (> 6 weeks post-surgery).
9. Male participants are eligible to participate if they agree to the following during the intervention period and for 6 months after the last dose of study treatment to allow for clearance of any altered sperm:
a. Refrain from donating sperm
PLUS either:
b. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
c. Must agree to use contraception/barrier
10. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
11. All subjects must agree not to share study medication.
12. All prior treatment-related toxicities must be ≤ Grade 1 at the time of enrolment except for alopecia. | |
| E.4 | Principal exclusion criteria | 1. Subject has received prior Venetoclax and/or anti BCMA treatment.
2. Participant has used an investigational drug or approved systemic anti-myeloma therapy within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug. The only exception is emergency use of a short course of corticosteroids (equivalent of Dexamethasone 40 mg/day for a maximum of 4 days) up to 7 days before treatment.
3. Participant has had plasmapheresis or radiation therapy within 7 days prior to first dose of study treatment
4. Participant has current corneal epithelial disease except mild changes in corneal epithelium
5. Participant has current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
6. Participant has a presence of active renal condition.
7. Participant has had major surgery ≤ 4 weeks prior to initiating study treatment.
8. Participant must not use contact lenses while participating in this study.
9. Participant has any evidence of active mucosal or internal bleeding or other gastrointestinal disease that may significantly alter the absorption of oral drugs.
10. Participant has evidence of cardiovascular risk including any of the following:
a. Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block
b. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within three (3) months prior to Screening.
c. Class III or IV heart failure as defined by the New York Heart Association functional classification system
d. Uncontrolled hypertension
e. Left ventricular Ejection Fraction ≤ 50%
11. Participant has known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to IMPs or drugs chemically related to IMPs, or any of the components of the study treatment
12. Participant has an invasive malignancy other than disease under study within 5 years before trial inclusion, except
- Adequately treated in situ carcinoma of the cervix uteri or the breast;
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
- Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment;
- Previous malignancy with no current evidence of disease, and which was confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
13. Participant is pregnant or lactating
14. Participants who have had prior allogeneic stem cell transplant.
15. Participants with symptomatic amyloidosis, active POEMS syndrome or active plasma cell leukaemia at the time of screening.
16. Participants with any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures.
17. Subject is known to be seropositive for HIV or hepatitis B, or hepatitis C.
18. Current immune or inflammatory conditions requiring immunosuppressive treatment.
19. Subject must not have received any live vaccines within 8 weeks prior to first dose of study treatment.
20. Subject must not use or anticipate the use of prohibited medications or foods during study participation.
21. Subject does not have a history of or show any signs of known meningeal/central nervous system involvement by myeloma.
22. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
a. Uncontrolled and/or active systemic infection requiring treatment.
b. Any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for the participation in this study.
23. Subject is known or suspected of not being able to comply with the study protocol. Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit or confound the protocol-specified assessments.
24. Treatment with any of the following within 7 days prior to the first dose of study drug:
a. moderate or strong cytochrome P450 3A (CYP3A) inhibitors
b. moderate or strong CYP3A inducers
25. Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
a. grapefruit or grapefruit products
b. Seville oranges (including marmalade containing Seville oranges)
c. star fruit
26. Participation in any other clinical trial (with the exclusion of observational studies) | |
| E.5 End points |
| E.5.1 | Primary end point(s) | The primary safety endpoints are defined as following:
a. Neutropenia grade 4 for more than 10 days
b. Thrombocytopenia grade 4 for more than 7 days
c. Any reported grade 4 non-hematologic toxicity
d. Any grade 3 reported non-hematological toxicity which is assigned with a possible relationship to the applied study drugs will be additionally reviewed by the Data Safety Monitoring Board (DSMB) for relevance if there is a potential relationship to any IMP in the opinion of the investigator.
Primary endpoints:
a. Percentage (number) of participants with dose limiting toxicities (DLTs)
b. Percentage (number) of participants with AEs, changes in clinical signs and laboratory parameters | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | 6 months after last patient in | |
| E.5.2 | Secondary end point(s) | The key secondary (efficacy) endpoints are defined as following:
a. Overall response rate (ORR)
b. Minimal residual disease (MRD) negativity rate
c. Progression-free survival (PFS)
d. Duration of response (DOR) | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | 6 months after last patient in | |
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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.8.3 | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | | last patient last visit (LPLV) | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 44 |
| E.8.9.1 | In the Member State concerned days | |
