A Phase 3, Multicenter, Randomized, Open Label Study of Venetoclax and Dexamethasone Compared with Pomalidomide and Dexamethasone in Subjects with t(11;14)-Positive Relapsed or Refractory Multiple Myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AbbVie Deutschland GmbH & Co. KG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Sep 2018 → ongoing

Decision date (initial)

2024-01-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AbbVie Inc.

External identifiers

EU CT number

2023-506112-40-00

EudraCT number

2017-003838-88

ClinicalTrials.gov

NCT03539744

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Pharmacogenetic, Safety, Dose response

To compare progression-free survival (PFS) in subjects with t(11;14)-positive MM treated with venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone.

Secondary objectives 1

1. The secondary objectives are to compare, between treatment arms (where applicable), the following: overall response rate (ORR); rate of very good partial response (VGPR) or better per International Myeloma Working Group (IMWG) criteria (see Appendix D); overall survival (OS); minimal residual disease (MRD) negativity rate; patient reported outcomes (PROs) evaluated using Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form (SF) 7a, Brief Pain Inventory – Short Form (BPI-SF), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) MM Module20 (EORTC QLQ-MY20), and EORTC QLQ Core 30 (EORTC QLQC30); duration of response (DOR); time to disease progression (TTP); time to response (TTR); pharmacokinetics (PK) of venetoclax; and safety.

Conditions and MedDRA coding

R/R Multiple Myeloma

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

AbbVie is committed to responsible clinical trial data sharing. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information. To learn more about the process, or to submit a request, visit https://www.abbvieclinicaltrials.com/hcp/data-sharing/ For details on when studies are available for sharing, visit https://vivli.org/ourmember/abbvie/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 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.
2. Subject must have received at least 2 consecutive cycles of lenalidomide and be relapsed/refractory to lenalidomide as defined by one of the following: Subject experienced PD on or within 60 days of completing treatment. Subject exhibited PR or better but relapsed within 6 months after stopping treatment.
3. Subject must have received at least 2 consecutive cycles of a proteasome inhibitor (bortezomib, carfilzomib or ixazomib).
4. Subject has measurable disease at Screening, defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL (≥5 g/L); OR Urine M-protein ≥200 mg/24 hours; OR Involved serum immunoglobulin free light chain (FLC) ≥10 mg/dL (100 mg/L), provided serum FLC ratio is abnormal
5. Subject has MM positive for t(11;14) as determined by an analytically validated FISH assay per centralized laboratory testing.
6. A negative serum pregnancy test for all female subjects (except those of non-childbearing potential) within 10 to 14 days prior to initiating therapy and a negative urine pregnancy test within 24 hours for all female subjects (except those of non-childbearing potential) at baseline prior to the first dose of study drug.
7. If female, subject must be either postmenopausal, OR permanently surgically sterile OR for women of childbearing potential practicing at least 2 protocol-specified methods of birth control that are effective from at least 30 days before starting study drugs through at least 30 days after the last dose of any study drug.
8. If male, and subject is sexually active with female partner(s) of childbearing potential, he must agree, from Study Day 1 through 30 days after the last dose of study drug, to practice the protocol-specified contraception.
9. Adult male or female subjects ≥18 years old.
10. Subjects should have laboratory values meeting the following criteria within the screening period prior to the first dose of study drug: Absolute neutrophil count (ANC) ≥1000/μL; subject may use growth factor support to achieve ANC eligibility criteria; Platelets: ≥50,000/mm3. For subjects with > 50% myeloma involvement in the marrow, a platelet count of ≥30,000 mm3. Subjects may not have received a platelet transfusion within 72 hours prior to the platelet count used for eligibility; Hemoglobin ≥8.0 g/dL; subject may receive red blood cell (RBC) transfusions in accordance with institutional guidelines to meet this criteria; AST and ALT ≤3 × upper limit of normal (ULN); Total bilirubin ≤1.5 x ULN (subjects with documented Gilbert's syndrome, may have bilirubin > 1.5 × ULN); Creatinine clearance ≥30 mL/min, measured by 24-hour urine collection or calculated using the Cockcroft-Gault formula); Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L) or ionized calcium (≤6.5mg/dL (≤1.6mmol/L).
11. Subjects should be willing or able to comply with procedures required in this protocol.
12. Subjects should be willing and able to receive antithrombotic prophylactic treatment.
13. Documented diagnosis of multiple myeloma based on standard IMWG criteria.
14. Subject has an ECOG performance status ≤ 2
15. Subject has documented disease progression on or within 60 days of completion of their last therapy.
16. Subject has received at least 2 prior lines of therapy. A line of therapy consists of at least 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens.
17. 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.

Exclusion criteria 18

1. Subject has history of treatment with venetoclax or another BCL-2 inhibitor or pomalidomide.
2. Subject has a history of other active malignancies, including myelodysplastic syndromes (MDS), within the past 3 years with the following exceptions: 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; or 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.
3. Subject has evidence of ongoing graft-versus-host disease (GvHD) if prior stem cell transplant (SCT).
4. Subject must not have received any live vaccines within 8 weeks prior to randomization
5. Subject has had prior treatment with the following: Allogeneic or syngeneic SCT within 16 weeks prior to randomization; or Autologous SCT within 12 weeks prior to randomization
6. Subject has known central nervous system involvement of multiple myeloma.
7. Subject has a history of clinically significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, pulmonary or hepatic disease within the last 6 months that, in the opinion of the investigator, would adversely affect participation in this study.
8. Subject has a history of known allergies, hypersensitivities, or intolerance to any of the study drug or excipients, or thalidomide derivatives.
9. Subject has the following conditions: Nonsecretory multiple myeloma; Active plasma cell leukemia i.e., either 20% of peripheral white blood cells or > 2.0 × 109/L circulating plasma cells by standard differential; Waldenström's macroglobulinemia; Primary amyloidosis; POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); Known human immunodeficiency virus (HIV) infection; Active hepatitis B (hepatitis B surface antigen [HBsAg] positive) or C infection based on screening central laboratory blood testing at screening; Significant cardiovascular disease, including uncontrolled angina, arrhythmia, recent myocardial infarction within 6 months prior to first dose, congestive heart failure NYHA Class ≥3; Major surgery within 4 weeks prior to first dose or planned during study participation; Acute infections within 14 days prior to first dose requiring therapy (antibiotic, antifungal, or antiviral); Uncontrolled diabetes or hypertension within 14 days prior to first dose; or Peripheral neuropathy ≥Grade 3 or ≥Grade 2 with pain within 2 weeks prior to first dose.
10. Female who is pregnant, breastfeeding, or considering becoming pregnant during the study and for at least 30 days after the last dose of study drug.
11. Male who is considering fathering a child or donating sperm and/or semen during the study and for at least 30 days after the last dose of study drug.
12. Subject who have been treated with any systemic anti-myeloma therapies within 5 half-lives or 2 weeks prior to randomization, whichever is longer (or 2 weeks if half-life unknown), and through the last dose of any study drug.
13. Subject who have been treated with anti-myeloma radiotherapy within 2 weeks prior to randomization.
14. Subject who have received corticosteroid therapy at a dose equivalent to > 4 mg daily of dexamethasone or a single dose of corticosteroid equivalent dose > 40 mg of dexamethasone within 2 weeks prior to randomization.
15. Subject who have used systemic strong or moderate inhibitor or inducer of cytochrome P450 (CYP) 3A within 1 week prior to the first dose of study drugs.
16. Subject who have used systemic strong inhibitor of CYP1A2 within 1 week prior to first dose.
17. Subject who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit within 3 days prior to first dose.
18. Subject who anticipate the use of prohibited medications or foods during study participation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is progression-free survival (PFS) per Independent Review Committee (IRC) based on IMWG criteria. PFS is defined as the time in days from subject randomization to the date of the first documented progressive disease (PD) or death due to any cause, whichever occurs first.

Secondary endpoints 12

1. Overall response rate (ORR) per the independent review committee (IRC)
2. Rate of very good partial response (VGPR) or better per the IRC
3. Overall survival (OS)
4. Minimal residual disease (MRD) negativity rate
5. Time to deterioration in disease symptoms as measured by the disease symptom domain of the EORTC QLQ-MY20
6. Time to deterioration in physical functioning as measured by the physical functioning domain of EORTC QLQ-C30
7. Other Patient reported outcomes (PROs) assessed using Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a, Brief Pain Inventory –Short Form [(BPI-SF]), EuroQoL 5 Dimension 5 Level (EQ5D5L) and remaining domains of EORTC QLQ-MY20, and EORTC QLQ-C30 survey instruments
8. Duration of response (DOR)
9. Time to disease progression (TTP)
10. Time to response (TTR)
11. Pharmacokinetics of venetoclax
12. Safety

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation

AbbVie Deutschland GmbH & Co. KG

Address

Knollstrasse

City

Ludwigshafen Am Rhein

Postcode

67061

Country

Germany

Scientific contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Public contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Third parties 8

Locations

7 EU/EEA countries · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 41 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications