A Phase 1b/2 Study of BMS-986158 Monotherapy and Combination with either Ruxolitinib or Fedratinib in Intermediate or High Risk Myelofibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bristol-Myers Squibb Services Unlimited Company

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Jun 2021 → ongoing

Decision date (initial)

2024-01-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-509635-89-00

EudraCT number

2020-002071-35

WHO UTN

U1111-1250-8029

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Dose response, Pharmacodynamic, Safety, Therapy, Pharmacogenomic

To assess the safety and tolerability, and to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D) of BMS-986158 in combination with ruxolitinib in previously untreated MF participants, and in combination with fedratinib in MF participants previously treated with ruxolitinib.

Secondary objectives 2

1. To assess the preliminary efficacy based on the reduction of spleen volume
2. To evaluate MF-associated symptoms

Conditions and MedDRA coding

DIPSS-Intermediate or High Risk Myelofibrosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Males and females of ≥ 18 years of age at the time of signing the ICF
2. Participant has diagnosis of PMF according to the 2017 World Health Organization criteria (Appendix 12), or diagnosis of post-ET or post-PV MF according to the IWG-MRT 2007 criteria (Appendix 13), confirmed by the most recent local pathology report.
3. Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 at Screening.
4. Part 1A, 1B, and 2B participants at Screening must have a DIPSS Risk Score of Intermediate-1 with symptoms, Intermediate-2, or High.
5. Part 2A participants must have had a DIPSS Risk Score of Intermediate-2 or High
6. Participant has a measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥ 450 cm3 by MRI or computed tomography (CT) scan assessment.
7. Not Applicable per Protocol Amendment 03, replaced with 10). In Part 1A- and 2A1-Ruxolitinib Combo cohorts: participants must not have been treated with JAK2 inhibitors prior to the start of treatment with BMS- 986158 in combination with ruxolitinib. In Part 2A2 (add-on to Ruxo), Ruxolitinib Combo cohorts: participants must have been treated with ruxolitinib for ≥ 3 months, and on a stable dose for ≥ 8 weeks prior to Screening with sub-optimal response defined as > 10% but < 35% spleen volume reduction by MRI/CT scan.
8. In Part 1B Fedratinib Combo cohorts, Part 2B1-Fedratinib Combo arm, and Part 2B2-BMS-986158 Mono arm: Participant has been previously exposed to ruxolitinib, and must meet at least 1 of the following criteria (I and/or II): I) Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response (refractory) defined as < 10% spleen volume reduction by MRI/CT scan or regrowth (relapsed) to these parameters following an initial response II) Treatment with ruxolitinib for ≥ 28 days complicated by any of the following (intolerant): a) Development of a RBC transfusion requirement (at least 2 units/month for 2 months) or b) 2) Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib
9. Must not be a candidate for, or must have refused, allogenic SCT
10. In Part 1A, 2A1, and 2A3 -Ruxolitinib Combo cohorts: participants must not have been exposed to JAK2 inhibitors prior to the start of treatment with BMS-986158 in combination with ruxolitinib. In Part 2A2 (add-on to Ruxo), Ruxolitinib Combo cohorts: participants must have been treated with ruxolitinib for ≥ 6 months, and on a stable dose ≥ 8 weeks prior to C1D1 with sub-optimal response defined as: (1) palpable spleen > 10 cm below left costal margin (LCM) on physical examination at Screening, or (2) palpable spleen 5-10 cm below LCM on physical examination at Screening and the presence of active MF symptoms at screening as measured by MFSAF (Appendix 9) and defined as 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 each.

Exclusion criteria 12

1. Participant with previous splenectomy.
2. In Part 1B-Fedratinib Combo cohorts, Part 2B1-Fedratinib Combo arm, and Part 2B2- BMS-986158 Mono arm: a) Participant with prior history of encephalopathy including WE. b) Participant with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not corrected prior to enrollment on the study (ie, C1D1). c) Participant who received ruxolitinib within 14 days prior to starting the treatment with BMS-986158 alone or in combination with fedratinib. Gradual tapering of ruxolitinib as per investigator's discretion is recommended, and must be completed at the latest 14 days prior to C1D1. Use of systemic steroids ≤ 10 mg/day prednisone or equivalent is allowed. d) Participant with previous exposure to JAK2 inhibitor(s) other than ruxolitinib.
3. Participant with previous exposure to a BET inhibitor.
4. Prior organ allograft or allogenic hematopoietic stem cell transplantation.
5. Participant with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis).
6. Participant has impaired cardiac function or clinically significant cardiac diseases a) Any of the following on 12-lead ECG prior to study drug administration, confirmed by repeat and central ECG laboratory assessment: QRS ≥ 120 msec or QTcF ≥ 460 msec
7. Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) 1 and 2 antibody a) Participants who are seropositive due to hepatitis B virus (HBV) vaccination are eligible. b) Participants who have no active viral infection and are under adequate prophylactics against HBV re-activation are eligible. c) Participants who are positive on anti-HCV IgG, but negative on viral RNA, and without morphologic changes in liver, are eligible.
8. History of medically significant thromboembolic events or bleeding diathesis within the past 6 months, such as cerebrovascular accident (including transient ischemic attacks), pulmonary embolism, pulmonary hemorrhage > 2 teaspoonfuls/24 hours or repeated pulmonary hemorrhage.
9. Participant with current or recent (within 1 month of study drug administration) GI disease such as symptomatic or uncontrolled ulcers (gastric or duodenal), particularly those with a history of and/or risk of perforation and GI tract hemorrhages, chronic or intermittent diarrhea, or uncontrolled disorders that increase the risk of diarrhea, such as inflammatory bowel disease. Non-chronic conditions (eg, infectious diarrhea) that are completely resolved for at least 2 weeks prior to starting study treatment are not exclusionary.
10. Previous SARS-CoV-2 infection within 10 days prior to Cycle 1 Day 1 for mild or asymptomatic illness or within 20 days prior to Cycle 1 Day 1 for severe/critical illness. Note: Acute symptoms must have resolved and based on investigator assessment in consultation with the Sponsor's Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving study treatment.
11. In Parts 1A and 2A: Participant with treatment or use of pharmaceutical, herbal agents, or food known to be strong inducers of CYP3A4 within 2 week or 5 half-lives (whichever is longer), strong inhibitors of CYP3A4 or P-gp within 1 week or 5 half-lives (whichever is longer).
12. Participants with uncontrolled endocrine disorder including thyroid disease or inadequate thyroid function. Note: Subclinical hypothyroidism (thyroid-stimulating hormone< 10 mIU/mL) or controlledhypothyroidism on appropriate thyroid supplementation are acceptable. Physical and Laboratory Test Findings a) Absolute neutrophil count< 1.0 × 109/L b) Hgb < 8 g/dL (Screening Hgb ≥ 14 days after last RBC transfusions)only for non-TD participants) c) WBC count > 100 × 109/L d) Myeloblasts ≥ 10% in peripheral blood e) AST and ALT ≥ 3.0 × upper limit of normal (ULN) f) Serum amylase or lipase > 1.5 × ULN g) Serum total bilirubin ≥ 1.5 × ULN (participant's total bilirubin between 1.5 to 3.0 × ULN are eligible if the direct bilirubin fraction is < 25% of the total bilirubin) h) Creatinine clearance (CrCl) < 50 mL/min (calculated using the Cockroft-Gault formula) within 14 days prior to first dose of study treatment. i) Serum albumin < 3.0 g/dL j) Participant with abnormal blood coagulation parameters: Prothrombin time (PT) such that international normalized ratio (INR) is > 1.5 × ULN or a partial thromboplastin time > 1.2 × ULN. k) PLT < 100 × 109/L for participants in the ruxolitinib cohorts Parts 1A and 2A1, and PLT < 75 × 109/L for participants in fedratinib cohorts Parts 1B and 2B (combination and monotherapy arms), for participants in the ruxolitinib cohort Part 2A2 (add-on to Ruxo) and Part 2A3 (only if PLT is not > 99 × 109/L) (Screening PLT ≥ 7 days after last PLT transfusions).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), Dose Limiting Toxicity (DLT), and AEs leading to discontinuation and death.

Secondary endpoints 3

1. ≥ 35% reduction in Spleen Volume Response measured by MRI or CT at the end of cycle 6 as assessed by central reader
2. ≥ 25% reduction in Spleen Volume Response measured by MRI or CT at the end of cycle 3 and 6 as assessed by central reader
3. ≥ 50% reduction in Total Symptom Score measured by MF Symptom Assessment Form (MFSAF) at the end of cycle 6

Investigational products

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

Test 3

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bristol-Myers Squibb Services Unlimited Company

Sponsor organisation

Bristol-Myers Squibb Services Unlimited Company

Address

Plaza 254, Blanchardstown Corporate Park 2 Blanchardstown Corporate Park 2

City

Dublin 15

Postcode

D15 T867

Country

Ireland

Scientific contact point

Organisation

Bristol-Myers Squibb Services Unlimited Company

Contact name

GSM-CT

Public contact point

Organisation

Bristol-Myers Squibb Services Unlimited Company

Contact name

GSM-CT

Third parties 12

Locations

7 EU/EEA countries · 21 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 44 files

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

Application history

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