A Phase 1b/2 Study of BGB-11417 as Monotherapy and in Various Combinations with Dexamethasone plus Carfilzomib, Dexamethasone plus Daratumumab, and Dexamethasone plus Pomalidomide in Multiple Myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BeOne Medicines AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 May 2024 → ongoing

Decision date (initial)

2024-04-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

BeiGene, Ltd

External identifiers

EU CT number

2023-507751-30-00

WHO UTN

U1111-1277-5444

ClinicalTrials.gov

NCT04973605

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Part 1 (Dose Escalation):
• To evaluate the safety and tolerability of sonrotoclax in combination with dexamethasone, dexamethasone plus carfilzomib, dexamethasone plus daratumumab, and dexamethasone plus pomalidomide in patients with relapsed/refractory (R/R) multiple myeloma (MM) and t(11;14)
• To determine the maximum tolerated dose (MTD)/maximum assessed dose (MAD) and recommended Phase 2 dose (RP2D) for sonrotoclax in combination with dexamethasone, dexamethasone plus carfilzomib, dexamethasone plus daratumumab, and dexamethasone plus pomalidomide in patients with R/R MM and t(11;14)

Part 2 (Cohort Expansion):
• To evaluate the safety and tolerability of sonrotoclax monotherapy, as well as the safety and tolerability of sonrotoclax in combination with dexamethasone at RP2D in patients with R/R MM and t(11;14)
• To evaluate the safety and tolerability of sonrotoclax in combination with dexamethasone plus carfilzomib at the recommended dose for the combination therapy in patients with R/R MM and t(11;14)
• To evaluate the efficacy of sonrotoclax as monotherapy, in combination with dexamethasone, and with dexamethasone plus carfilzomib in patients with R/R MM and t(11;14) as measured by overall response rate and additional response rates

Secondary objectives 3

1. For Part 1 (Dose Escalation): To assess the pharmacokinetics (PK) of sonrotoclax in combination with dexamethasone, dexamethasone plus carfilzomib, dexamethasone plus daratumumab, and dexamethasone plus pomalidomide
2. For Part 2 (Cohort Expansion): To evaluate the efficacy of sonrotoclax as monotherapy, in combination with dexamethasone, and with dexamethasone plus carfilzomib in patients with R/R MM and t(11;14) as measured by duration of response, time to response, and time to event outcomes
3. For Part 2 (Cohort Expansion): To evaluate the efficacy and safety between sonrotoclax in combination with dexamethasone plus carfilzomib versus dexamethasone plus carfilzomib

Conditions and MedDRA coding

relapsed or refractory multiple myeloma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
2. A confirmed diagnosis of multiple myeloma
3. Measurable disease defined as: (a) M-spike ≥ 500 mg/dL, or (b) Urine protein M-spike of ≥ 200 mg/day, or (c) Serum free light chains ≥ 10 mg/dL, and an abnormal κ:λ ratio
4. Patient has documented relapsed or progressive MM on or after any regimen or who are refractory to the most recent line of therapy. 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. 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.
5. Patients in Part 1 (all cohorts) 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 therapies.
6. Patients in Part 2 (Cohorts 1 and 2) 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 therapies.
7. Patients in Part 2 (Cohorts 3, 4 and 5): (i) Should have relapsed or progressive disease and have had ≥ 1 prior line of therapy. Patients must have been exposed to a combination therapy containing an anti-CD38 monoclonal antibody. Prior treatment with carfilzomib is allowed, but the patient must not be considered carfilzomib refractory by the investigator.
8. Positivity for t(11;14) translocation must be confirmed by a validated FISH assay in a predefined central laboratory: (a) A fresh bone marrow aspirate sample must be collected at screening and sent to central laboratory for t(11;14) FISH testing; (b) Enrollment requires centrally confirmed t(11;14) results.
9. Adequate organ function defined as: (a) Hemoglobin ≥ 8.0 g/dL within 7 days before first dose of study treatment (transfusions, in accordance with institutional guidelines, are permitted); (b) Platelet count ≥ 75,000/μL within 7 days before first dose of study treatment, independent of growth factor support and transfusions; (c) Absolute neutrophil count (ANC) ≥ 1000/mm3 within 7 days before first dose of study treatment; (d) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) and total bilirubin ≤ 2.0 x ULN; (e) Creatinine clearance ≥ 45 mL/min/1.73 m2 as calculated by the MDRD-6 formula.

Exclusion criteria 5

1. Patient has any of the following conditions: (a) Non secretory MM (Serum free light chains < 10 mg/dL); (b) Solitary plasmacytoma; (c) Active plasma cell leukemia (5% of peripheral white blood cells); (d) Waldenström macroglobulinemia; (e) Amyloidosis; (f) Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome.
2. Chronic respiratory disease that requires continuous oxygen and/or respiratory failure requiring assisted ventilation
3. Significant cardiovascular disease, including but not limited to: (a) Myocardial infarction ≤ 6 months before screening; (b) Ejection fraction ≤ 50%; (c) Unstable angina ≤ 3 months before screening; (d) New York Heart Association Class III or IV congestive heart failure; (e) History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes); (f) Heart rate-corrected QT interval > 480 milliseconds based on Fridericia’s formula; (g) History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; (h) Uncontrolled hypertension at screening, defined as systolic blood pressure > 140 mmHg and diastolic blood pressure > 90 mmHg by ≥ 2 consecutive measurements.
4. Positive human immunodeficiency virus serology (HIVAb) status.
5. Serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows: (a) Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients 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. (b) Presence of HCV antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (limitation of sensitivity < 15 IU/mL).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Part 1 (Dose Escalation): Safety and tolerability of sonrotoclax in combination with dexamethasone, dexamethasone plus carfilzomib, dexamethasone plus daratumumab, and dexamethasone plus pomalidomide as assessed by (a) Protocol-defined dose limiting toxicities (DLTs), and (b) The incidence, timing, and severity of treatment-emergent adverse events (TEAEs), serious adverse events, adverse events leading to discontinuation, and adverse events of special interest (AESIs) per NCI CTCAE v5.0
2. Part 2 (Cohort Expansion): Safety and tolerability of sonrotoclax at the recommended Phase 2 dose (RP2D) as monotherapy, in combination with dexamethasone, and in combination with dexamethasone plus carfilzomib at the recommended dose combination(s), as assessed based on the incidence, timing, and severity of DLTs (for sonrotoclax monotherapy only), TEAEs, serious adverse events, adverse events leading to discontinuation, and AESIs according to NCI-CTCAE v5.0
3. Part 2 (Cohort Expansion): Overall response rate (ORR), defined as the proportion of patients who achieved a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per International Myeloma Working Group (IMWG) guidelines
4. Part 2 (Cohort Expansion): VGPR or better response rate, defined as the proportion of patients with a documented VGPR or better (including sCR, CR, and VGPR)
5. Part 2 (Cohort Expansion): CR or sCR rate, defined as the proportion of patients with a documented CR or sCR.

Secondary endpoints 5

1. Part 1 (Dose Escalation): Derived PK parameters of sonrotoclax, including: (a) For a single dose: area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUClast), maximum observed plasma concentration (Cmax), and time to reach Cmax (tmax) as appropriate. (b) After steady-state (ss): AUClast,ss, Cmax,ss, trough plasma concentration (Ctrough) ss, and tmax,ss. Other PK parameters may be reported.
2. Part 2 (Cohort Expansion): Time to response (TTR) as assessed by investigator, defined as the time from start of treatment (for nonrandomized cohorts) or date of randomization (for randomized cohorts [Part 2 Cohorts 3, 4, and 5]) to first documentation of response of PR or better.
3. Part 2 (Cohort Expansion): Duration of response (DOR) is defined as the time from the date of the first documented response (PR or better) after treatment initiation until the date of first documented disease progression or death due to any cause, whichever occurs first.
4. Part 2 (Cohort Expansion): Progression-free survival (PFS) as assessed by investigator, defined as time from start of treatment (for nonrandomized cohorts) or date of randomization (for randomized cohorts [Part 2 Cohorts 3, 4, and 5]) to the first documentation of disease progression or death, whichever occurs first.
5. Part 2 (Cohort Expansion): Overall survival (OS), defined as the time from start of treatment (for nonrandomized cohorts) or date of randomization (for randomized cohorts [Part 2 Cohorts 3, 4, and 5]) to the date of death due to any cause.

Investigational products

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

Test 1

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BeOne Medicines AG

Sponsor organisation

BeOne Medicines AG

Address

Aeschengraben 27

City

Basel

Postcode

4051

Country

Switzerland

Scientific contact point

Organisation

BeOne Medicines AG

Contact name

BeOne Medical Officer

Public contact point

Organisation

BeOne Medicines AG

Contact name

BeOne Medical Officer

Third parties 17

Locations

5 EU/EEA countries · 19 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 66 files

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

Application history

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