| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to assess the safety and tolerability of BMS-986179 administered alone and/or in combination with nivolumab. |
|
| E.2.2 | Secondary objectives of the trial |
-) To characterize the PD activity of BMS-986179 administered alone and in combination with nivolumab
-) To assess the preliminary anti-tumor activity of BMS-986179 in combination with nivolumab as measured by objective response rate (ORR), DOR, and progression-free survival rate (PFSR)
-) To characterize the PK and immunogenicity of BMS-986179 administered alone and in
combination with nivolumab
-) To characterize the immunogenicity of nivolumab when administered in combination with
BMS-986179 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
|
| E.3 | Principal inclusion criteria |
1. Signed Written IC
2. Population
a) Subjects must be > 18 years old/have histologic or cytologic confirmation of a malignancy that is advanced (metastatic and/or unresectable) with measureable disease and have at least 1 lesion that is biopsy-accessible.
b) Part 1A/Part 1B:
i) Subjects must have received, and then progressed/been intolerant to, at least 1 standard treatment regimen in the advanced or metastatic setting, if such a therapy exists and have been considered for all other potentially efficacious therapies prior to enrollment. Subjects who are ineligible for standard therapy (due to medical factors) will be allowed to enroll provided their refusal/ineligibility is documented in records.
ii) All solid tumor histologies will be permitted except for subjects with primary CNS tumors or with CNS metastases as the only site of active disease.
c) Part 2:
i) For ovarian cancer
(1) Subjects must have received and progressed/been intolerant of at least 1 prior platinum-containing treatment regimen and have been considered for all other potentially efficacious therapies.
(2) Subjects who are sensitive to platinum must have received at least 2 prior platinum-containing lines of treatment.
ii) For CRC:
(1) Subjects must have received and progressed/been intolerant of at least 1 standard systemic therapy for metastatic and/or unresectable disease (or have progressed within 6 months of adjuvant therapy) and have been considered for all other potentially efficacious therapies.
(2) Subjects must have known KRAS mutation status.
iii) For gastric cancer:
(1) Subjects must have received and progressed/been intolerant of at least 1 prior standard systemic therapy for metastatic and/or unresectable disease (or have progressed within 6 months of adjuvant therapy) and have been considered for all other potentially efficacious therapies.
(a) Subjects must have known HER2 mutation status. Subjects with tumors overexpressing HER2 must have received prior HER2 therapy or have a medical reason for ineligibility.
iv) For pancreatic cancer:
(1) Subjects must have received and progressed/been intolerant of (or not be a candidate for) at least 1 prior standard therapy and have been considered for all other potentially efficacious therapies.
d) Subjects must have an Eastern Cooperative Oncology Group performance status of ≤ 1.
e) Subjects must have at least one lesion with measureable disease
f) Subjects who have had prior exposure to therapy with any agent specifically targeting checkpoint pathway inhibition are permitted after a washout period of any time > 4 weeks from the last treatment.
g) Subjects with prior therapy with any agent specifically targeting T-cell co-stimulation pathways such as anti-glucocorticoid induced tumor necrosis factor receptor, anti-CD137, or anti-OX40 antibody, with exceptions, are permitted after a washout period of any time > 4 weeks from the last treatment.
h) Prior palliative radiotherapy must have been completed at least 2 weeks prior to first dose of the study drug.
i) Subject must consent to a pre-treatment tumor biopsy. Subjects must also consent to the acquisition of existing formalin-fixed paraffin-embedded tumor tissue (if available), either a block or 15 to 20 unstained slides, for performance of correlative studies.
j) Pre-treatment biopsy tissue may have been collected at any time during the screening period prior to the first dose of the study drug.
k) Subjects must have adequate organ function.
l) Ability to comply with treatment, PK, immunogenicity, biomarker, and PD sample collection, and required study follow-up.
m) Subject re-enrollment: This study permits the re-enrollment of a subject who has discontinued the study as a pre-treatment failure.
3. Age and Reproductive Status
a) Subjects must be males and females ages ≥ 18 years at the time of informed consent.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the start of the study drug.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus > 5 half-lives of BMS-986179 plus 30 days (for subjects who discontinue during the monotherapy lead-in) or > 5 months after the last dose of nivolumab (for subjects who discontinue during combination therapy).
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus > 5 half-lives of BMS-986179 plus 90 days (for subjects who discontinue during the monotherapy lead-in) > 7 months after the last dose of nivolumab (for subjects who discontinue during combination therapy).
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements and still undergo pregnancy testing as described. |
|
| E.4 | Principal exclusion criteria |
1. Target Disease Exceptions
a) Subjects with known or suspected CNS metastases, untreated CNS metastases, or with the CNS as the only site of disease are excluded. However, subjects with controlled brain metastases will be allowed to enroll.
b) Subjects with carcinomatous meningitis are excluded.
c) Subjects who have participated in any prior clinical study with nivolumab in which OS is listed as the primary or co-primary endpoint and which has not completed analysis based on the primary endpoint are excluded.
d) For pancreatic cancer:
Subjects with clinically relevant ascites at baseline (defined as requiring paracentesis) or with moderate radiographic ascites are excluded.
2. Medical History and Concurrent Diseases
a) Subjects with a prior malignancy, different from the one used for enrollment in this study,
diagnosed less than 2 years ago are excluded. Subjects with second malignancies diagnosed more than 2 years ago who have received therapy with curative intent with no evidence of disease during the interval and who are considered by the investigator to present a low risk for recurrence will be eligible.
b) Subjects with other active malignancy requiring concurrent intervention are excluded.
c) Subjects with prior organ allograft are excluded.
d) Subjects who have received prior anti-cancer treatments are permitted
e) Subjects who have received prior therapy with an anti-CD73 antibody, an anti-CD39 antibody, or an adenosine 2A receptor inhibitor are excluded.
f) Subjects with a prior history of deep vein thrombosis within the last 6 months, or arterial thrombus at any time are excluded.
g) Subjects with active, known or suspected autoimmune disease, with a few exceptions.
h) Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity are excluded.
i) Subjects with chronic obstructive pulmonary disease requiring recurrent steroids bursts or chronic steroids at doses greater than 10 mg/day of prednisone or the equivalent are excluded.
j) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration except for adrenal replacement steroid doses > 10 mg daily prednisone equivalent in the absence of active autoimmune disease are excluded. Note: Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating study drug is permitted.
k) Subjects with uncontrolled or significant cardiovascular disease are excluded.
l) Subjects with active hepatitis as evidenced by the following are excluded:
i) Positive test for hepatitis B surface antigen
ii) Positive test for hepatitis C antibody and/or qualitative viral load
m) Subjects with evidence of active bacterial, viral, or fungal infections less or equal to 7 days prior to
initiation of study drug therapy are excluded.
n) Subjects with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are excluded.
o) Subjects with evidence or history of active or latent tuberculosis infection are excluded.
p) Subjects who have undergone any major surgery within 4 weeks of study drug administration are excluded. Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of the study drug.
q) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 4.03) or baseline before administration of the study drug.
r) Subjects who have used non-oncology vaccines containing live virus within 12 weeks prior to study drug are excluded.
s) Subjects who have used packed red blood cells or received a platelet transfusion within 2 weeks prior to the first dose of the study drug are excluded.
t) Subjects with a known or underlying medical condition that, in the opinion of the investigator or Sponsor, could make the administration of study drug hazardous to the subjects, or could adversely affect the ability of the subject to comply with or tolerate the study, are excluded.
3. Allergies to nivolumab and significant reaction to prior anti-cancer immune modulating therapies.
4. Other Exclusion Criteria
a) Subjects who are prisoners or are involuntarily incarcerated are excluded.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness are excluded.
c) Subjects who are unable to comply with restrictions and prohibited activities/treatments are excluded. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of the study is to assess the safety and tolerability of BMS-986179 administered alone and/or in combination with nivolumab. The assessment of safety will be based on the incidence of AEs, SAEs, AEs leading to discontinuation, and deaths. In addition, clinical laboratory test abnormalities will be examined. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The first secondary objective (PD effect of CD73 inhibition) will be measured by CD73 enzyme assays and CD73 IHC in pre- and on-treatment tumor biopsies.
The anti-tumor activity of BMS-986179 in combination with nivolumab will be measured by ORR, DOR, and PFSR at 24 weeks and will be based on RECIST 1.1 for solid tumors. Disease assessment with CT and/or MRI as appropriate will be performed at baseline, every 8 weeks from the start of combination treatment for the Q1W and Q2W regimens, or every 9 weeks from the start of combination treatment for the Q3W regimen until treatment discontinuation or completion, and then every 12 weeks for the first year until further disease progression, start of a new treatment, lost to follow-up, or death, whichever comes first.
The PK will be characterized by assessment of PK parameters of BMS-986179, and immunogenicity will be assessed by the frequency of positive ADA to BMS-986179 and nivolumab. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | 13 |
| 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 | 20 |
| 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 |
| Canada |
| Israel |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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