A Phase 1b/2 Study of Sonrotoclax (BGB-11417) as Monotherapy and in Various Combinations With Dexamethasone Plus Carfilzomib, Dexamethasone Plus Daratumumab, and Dexamethasone Plus Pomalidomide in Multiple Myeloma

Official title

A Phase 1b/2 Dose-Escalation and Cohort-Expansion Study to Determine the Safety and Efficacy of BGB-11417as Monotherapy, in Combination With Dexamethasone, Dexamethasone/Carfilzomib, Dexamethasone/Daratumumab, and Dexamethasone/Pomalidomide in Patients With Relapsed/Refractory Multiple Myeloma and t(11;14)

Overview

The purpose of this study is to assess the safety, tolerability, and efficacy of sonrotoclax as monotherapy and in various combinations in patients with relapsed/refractory (R/R) multiple myeloma (MM) and chromosomal translocation t(11;14). The study investigates sonrotoclax alone and in combination with dexamethasone and other agents, including carfilzomib, daratumumab, and pomalidomide.

Detailed description

Our company, previously known as BeiGene, is now officially BeOne Medicines. Because some of our older studies were sponsored under the name BeiGene, you may see both names used for this study on this website.

Interventions

• Drug Sonrotoclax
  Administered orally daily
• Drug Dexamethasone
  Once weekly either orally or intravenously
• Drug Carfilzomib
  Administered intravenously weekly
• Drug Daratumumab
  Administered subcutaneously weekly
• Drug Pomalidomide
  Administered orally daily

Primary outcome measures

• Part 1: Number Of Participants Experiencing Dose-limiting Toxicities (DLTs) [Time frame: Up to 28 days]
• Part 1 And 2: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Adverse Events Leading to Discontinuation and Adverse Events of Special Interest (AESIs). [Time frame: Up to 30 days after last dose of study drug]
• Part 2: Overall response rate (ORR) as Assessed by Investigator [Time frame: Approximately 4 years]
• Part 2: Very Good Partial Response (VGPR) or Better Response Rate as Assessed by Investigator [Time frame: Upon study termination (Baseline up to first documentation of disease progression [PD] or death from any cause [approximately 4 years]]
• Part 2: Complete Response (CR) or Stringent Complete Response (sCR) as Assessed by Investigator [Time frame: Upon study termination (Baseline up to first documentation of disease progression [PD] or death from any cause [approximately 4 years])]

Secondary outcome measures (11)

• Part 1: Area under the plasma concentration-time curve time 0 to the last measurable concentration (AUClast) After a Single Dose of Sonrotoclax [Time frame: Cycle 1 (each cycle is up to 28 days)]
• Part 1: Maximum observed plasma concentration (Cmax) After a Single Dose of Sonrotoclax [Time frame: Cycle 1 (each cycle is up to 28 days)]
• Part 1: Time to reach Cmax (tmax) After a Single Dose of Sonrotoclax [Time frame: Cycle 1 (each cycle is up to 28 days)]
• Part 1: At Steady-state: AUC last, ss [Time frame: Cycle 2 (each cycle is up to 28 days)]
• Part 1: At Steady-state: Cmax, ss [Time frame: Cycle 2 (each cycle is up to 28 days)]
• Part 1: At Steady-state: trough plasma concentration (Ctrough) ss [Time frame: Cycle 2 (each cycle is up to 28 days)]
• Part 1: At Steady-state: time to reach Cmax (tmax,ss) [Time frame: Cycle 2 (each cycle is up to 28 days)]
• Part 2: Time to response (TTR) as Assessed by Investigator [Time frame: Approximately 4 years]
• Part 2: Duration of response (DOR) as Assessed by Investigator [Time frame: Approximately 4 years]
• Part 2: Progression-free survival (PFS) as Assessed by Investigator [Time frame: Approximately 4 years]
• Part 2: Overall survival (OS) as Assessed by Investigator [Time frame: Approximately 4 years]

Eligibility criteria

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• A confirmed diagnosis of multiple myeloma (must have an M-component in serum and/or urine)
• Measurable disease defined as:

i. M-spike ≥ 500mg/dL, or ii. Urine protein M-spike of ≥ 200 mg/day, or iii. Serum free light chains ≥ 10 mg/dL, and an abnormal κ:λ ratio

• Participant has documented relapsed or progressive MM on or after any regimen or who are refractory to the most recent line of therapy.

i. Relapsed MM is defined as previously treated MM that progresses and requires initiation of salvage therapy but does not meet the criteria for refractory MM.

ii. Refractory MM is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease) while on primary or salvage therapy or progresses within 60 days of last therapy.

• In Part 1 and Part 2 Cohorts 1 and 2 participants should have relapsed or progressive disease and have had ≥ 3 prior lines of therapy including a proteasome inhibitor, an IMiD, and an anti-CD38 monoclonal antibody, and no more available approved therapies.
• Participants in Part 2 Cohorts 3, 4, and 5 should have relapsed or progressive disease and have had ≥ 1 prior line of therapy. Prior treatment with carfilzomib is allowed but the patient must not be considered carfilzomib refractory by the investigator.
• Participants in Part 2 Cohorts 6 and 7 should have relapsed or progressive disease and have had 1 to 3 prior lines of therapy and previously treated with a proteasome inhibitor and an IMiD
• Positivity for t(11;14) translocation must be confirmed by validated fluorescence in situ hybridization (FISH) testing assay in a pre-defined laboratory

a. fresh bone marrow aspirate sample must be collected at screening and sent to central laboratory for t(11;14) FISH testing.

• Adequate organ function defined as:

• Hemoglobin ≥ 8.0 g/dL within 7 days before first dose of study treatment, (transfusions, in accordance with institutional guidelines, are permitted)
• Platelet count ≥ 75,000/μL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions
• Absolute neutrophil count (ANC) ≥ 1000/mm\^3 within 7 days before first dose of study treatment
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) and total bilirubin ≤ 2.0 x ULN N (total bilirubin must be < 3 x ULN for patients with Gilbert's syndrome)

Exclusion criteria

• Participant has any of the following conditions:

• Non secretory MM (Serum free light chains < 10 mg/dL)
• Solitary plasmacytoma
• Active plasma cell leukemia (ie, either 20% of peripheral white blood cells or > 2.0 x 109/L circulating plasma cells by standard differential)
• Waldenström macroglobulinemia (WM)
• Amyloidosis.
• Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome
• Chronic respiratory disease that requires continuous oxygen
• Significant cardiovascular disease, including but not limited to:

• Myocardial infarction ≤ 6 months before screening
• Ejection fraction ≤ 50%
• Unstable angina≤ 3 months before screening
• New York Heart Association Class III or IV congestive heart failure
• History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
• Heart rate-corrected QT interval > 480 milliseconds based on Fridericia's formula
• History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
• Uncontrolled hypertension at screening, defined as systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg by ≥ 2 consecutive measurements. Prior therapy with sonrotoclax or other agents inhibiting BCL2 activity (eg, venetoclax)
• Known infection with human immunodeficiency virus (HIV)
• Serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows:

• Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Participants with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable (limitation of sensitivity < 20 IU/mL) ,), and if they are willing to undergo monthly monitoring for HBV reactivation.
• Presence of HCV antibody. Participants with presence of HCV antibody are eligible if HCV RNA is undetectable (limitation of sensitivity < 15 IU/mL).

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 23 centers

• Peking University Third Hospital — Beijing
• Beijing Chao Yang Hospital — Beijing
• Peking University Peoples Hospital — Beijing
• Chongqing Cancer Hospital — Chongqing
• Fujian Medical University Union Hospital — Fuzhou
• The First Affiliated Hospital of Xiamen University — Xiamen
• Sun Yat Sen University Cancer Center — Guangzhou
• The Second Hospital of Hebei Medical University — Shijiazhuang
• … and 15 more centers

United States · 16 centers

• University of Alabama At Birmingham Hospital — Birmingham
• City of Hope National Medical Center — Duarte
• City of Hope Irvine Lennar — Irvine
• University of Miami — Miami
• Emory University Winship Cancer Center — Atlanta
• University of Chicago Medical Center — Chicago
• Massachusetts General Hospital — Boston
• Washington University School of Medicine — St Louis
• … and 8 more centers

Brazil · 7 centers

• Hospital Sirio Libanes Brasilia — Brasília
• Instituto Dor de Pesquisa E Ensino Distrito Federal — Brasília
• Centro Gaucho Integrado de Oncologia Hospital Mae de Deus — Porto Alegre
• Hospital Sao Rafael (Rede Dor) — Salvador
• Hospital Sirio Libanes — São Paulo
• Instituto Dor de Pesquisa E Ensino Sao Paulo — São Paulo
• Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein — São Paulo

Australia · 6 centers

• Canberra Hospital — Garran
• Nepean Hospital — Kingswood
• Monash Health — Clayton
• St Vincents Hospital Melbourne — Fitzroy
• The Alfred Hospital — Melbourne
• Royal Perth Hospital — Perth

Italy · 6 centers

• Azienda Ospedaliera Universitaria Delle Marche — Ancona
• Azienda Ospedaliera Policlinico Di Bari — Bari
• Policlinico Sorsola Malpighi, Aou Di Bologna — Bologna
• Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst — Meldola
• Istituto Europeo Di Oncologia — Milan
• Istituto Di Candiolo Irccs — Torino

South Korea · 5 centers

• Samsung Medical Center — GangnamGu
• The Catholic University of Korea, Seoul St Marys Hospital — SeochoGu
• Severance Hospital Yonsei University Health System — SeodaemunGu
• Seoul National University Hospital — Seoul
• Asan Medical Center — SongpaGu

Germany · 4 centers

• Universitaetsklinikum Aachen — Aachen
• Universitatsklinikum Carl Gustav Carus An Der Technischen Universitat Dresden — Dresden
• Universitatsklinikum Hamburg Eppendorf — Hamburg
• Universitatsklinikum Wurzburg — Würzburg

United Kingdom · 4 centers

• Oxford University Hospitals Nhs Trust Churchill Hospital — Headington
• … and 3 more centers

Canada · 3 centers

• Cross Cancer Institute — Edmonton
• British Columbia Cancer Agency the Vancouver Centre — Vancouver
• Princess Margaret Cancer Centre — Toronto

France · 3 centers

• Hopital Claude Huriez Chu Lille — Lille
• Centre Hospitalier Universitaire Nantes Hotel Dieu — Nantes
• Chu de Poitiers Site de La Mileterie — Poitiers

Spain · 3 centers

• Hospital Clinic de Barcelona — Barcelona
• Hospital San Pedro de Alcantara — Cáceres
• Hospital Universitario Virgen de La Victoria — Málaga

Greece · 2 centers

• University Hospital of Alexandroupolis — Alexandroupoli
• General Hospital of Athens Alexandra — Athens

Singapore · 1 center

• National University Hospital Singapore — Singapore

Identifiers

NCT: NCT04973605 · BGB-11417-105 · 2023-507751-30-00 · 2021-003614-39 · U1111-1277-5444 · CTR20231932

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)
• NMPA/CDE CTR20231932 (chinadrugtrials.org.cn platform)

View this study on ClinicalTrials.gov ↗