| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| DIPSS-Intermediate or High Risk Myelofibrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| DIPSS-Intermediate or High Risk Myelofibrosis |
|
| 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 | 10000879 |
| E.1.2 | Term | Acute myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028537 |
| E.1.2 | Term | Myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose Escalation (Part 1)
- To assess the safety tolerability, and to determine the MTD and/or RP2D of BMS-986158 in combination with ruxolitinib in previously untreated (1L) MF participants, and in combination with fedratinib in ruxolitinib-exposed (2L) MF participants.
Dose Expansion (Part 2)
- To further determine the safety and tolerability of BMS-986158 in combination with ruxolitinib in 1L or
as an “add-on” to ruxolitinib in MF participants, and in combination with fedratinib, or as monotherapy, in 2L MF participants at the RP2Ds. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the preliminary efficacy of BMS-986158 in combination with ruxolitinib in 1L or as an “add-on” to
ruxolitinib in MF participants or in combination with fedratinib, or as monotherapy, in 2L MF participants, based on SVR (modified IWG-MRT 2013 in Appendix 8).
-To assess the preliminary efficacy of BMS-986158 in Part 2A2 (add-on to ruxolitinib) participants based on SVR.
- To evaluate MF-associated symptoms as measured by the MFSAF of participants treated with BMS-986158 monotherapy and in combination with either ruxolitinib or fedratinib in Part 2.
- Improvement in anemia in Part 2 (modified IWG-MRT 2013) based on pre-defined changes in both TI participants and TD participants.
- To characterize the PK of BMS-986158 in combination with ruxolitinib and in combination with fedratinib and in monotherapy.
- SDPFS of participants treated with BMS-986158 in combination with either ruxolitinib or fedratinib and in monotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. |
|
| E.4 | Principal exclusion criteria |
1) Ppt with previous splenectomy.
2) In Part 1B-Fedratinib Combo cohorts, Part 2B1-Fedratinib Combo arm, and Part 2B2- BMS-986158 Mono arm:
a) Ppt 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:
i) QRS 120 msec
ii) 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 controlled hypothyroidism 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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Incidence of AEs, SAEs, AEs meeting protocol-defined DLT criteria, AEs leading to discontinuation, and death.
• Incidence of AEs, SAEs, AEs leading to discontinuation, and death.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| up to progressive disease, but it is expected to last from 12 months up to 24 months + 30-90 days. = up to 27 months |
|
| E.5.2 | Secondary end point(s) |
1 SVR at end of Cycle 6 (and response rate defined as proportion of participants with SVR ≥ 35%) by MRI (preferred) or CT (if MRI is contraindicated) assessed by BICR.
2SVR at end of Cycle 3 and 6 (and response rate defined as proportion of participants with SVR = 25%) by MRI (preferred) or CT (if
MRI is contraindicated and if CT is allowed by local guidelines) assessed by
BICR
3 SRR and additional measures based on TSS measured by MFSAF; SRR is calculated at the end of Cycle 6 (and defined as the proportion of participants with ≥ 50% reduction in TSS).
4 For TI, proportion of participants having ≥ 2.0 g/dL Hgb increase over baseline, and for TD, proportion of participants becoming TI as measured by absence of RBC transfusions, ESA and hydroxyurea, over any consecutive 12-week period.
5 Summary of PK parameters of BMS-986158 in combination with ruxolitinib and in combination with fedratinib, and in BMS-986158 monotherapy.
6 Time from Dose 1, Day 1 to death due to any reason or disease progression (per modified IWG-MRT 2013) assessed by BICR; median SDPFS and SDPFS rates at 6 months and 12 months.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 SVR – Up to cycle 6
2 SRR – up to cycle 6
3 SVR - Up to cycle 3 and 6
4 Improvement in Anemia OR “For TI, proportion of …” – the endpoint assessment timeframe can be aligned with the other secondary efficacy endpoints, such as SVR at Cycle 6, and repeated up to 24 months
5 PK – Up to 24 months
6 PK SDPFS – Up to 12 months
|
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 |
| This study is a multicenter, open-label, Phase 1b/2, dose escalation and expansion study |
|
| 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 | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Poland |
| Romania |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Participants will be treated up to progression of disease, withdrawal of consent, treatment discontinuation for any reason, or end of study (as defined in Section 5.3 of the protocol), whichever occurs earlier. An end-of-treatment evaluation should be performed for participants who are withdrawn from treatment for any reason as soon as possible (≤ 28 days) after the decision to permanently discontinue treatment has been made. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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