IRB Study Number BRMY1524
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To determine the safety, tolerability and dose for further development of BMS-986507 in combination with:
Group A: Osimertinib in participants with locally advanced or metastatic EGFRmt NSCLC
Group B: Pembrolizumab in participants with locally advanced or metastatic EGFRwt NSCLC
To establish the MTD and/or recommended doses for further evaluation (RDE) of BMS-986507 in combination with:
Group B: Pembrolizumab in participants with locally advanced or metastatic EGFRwt NSCLC (Part 1 Dose Escalation)
Secondary Objectives
To determine the PK profile of BMS-986507 following IV administration in combination with:
Group A: Osimertinib in participants with locally advanced or metastatic EGFRmt NSCLC
Group B: Pembrolizumab in participants with locally advanced or metastatic EGFRwt NSCLC
To assess the preliminary antitumor activity of BMS986507 administered in combination with:
Group A: Osimertinib in participants with locally advanced or metastatic EGFRmt NSCLC
Group B: Pembrolizumab in participants with locally advanced or metastatic EGFRwt NSCLC
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/ IEC-approved written informed consent form (ICF) in accordance with regulatory, local, and institutional guidelines. This ICF must be obtained before performing any protocol-related procedures that are not part of normal patient care.
2) Type of Participant and Target Disease Characteristics
a) Participants in all parts of the study must have at least one measurable lesion per response evaluation criteria in solid tumors (RECIST) v1.1 (Appendix 6)
b) Participants must have an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (Appendix 5).
c) Participants must have a life expectancy of at least 3 months at the time of the first dose.
d) Fresh or archival FFPE tumor tissue obtained within 6 months prior to enrollment is required. Refer to Section 5.1.1
e) Group A: EGFRmt NSCLC
i) Participants must have pathologically confirmed locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation in exon 21, either alone or in combination with other EGFR mutations, which may include T790M in exon 20. Participants with other EGFR mutations (including but not limited to exon 20 insertion, exon 21 L861Q, exon 18 G719X, and exon 20 S768I mutations, etc.) will also be allowed.
ii) Participants must not have received any other prior systemic cancer therapy for locally advanced or metastatic NSCLC, including tyrosine kinases inhibitors.
iii) Participants must be eligible to receive first-line treatment with Osimertinib.
f) Group B: EGFRwt NSCLC
i) Participants must have pathologically confirmed locally advanced or metastatic NSCLC.
ii) Participants must not have received any other prior systemic cancer therapy for locally advanced or metastatic NSCLC (Part 2 Dose Expansion only)
iii) Participants must have experienced radiographically documented progressive disease on or after the most recent therapy (Part 1 Dose Escalation only)
iv) Participants who have received pembrolizumab or pembrolizumab with chemotherapy in prior therapies, must have received them for at least 3 cycles, with no evidence of disease progression (Part 1 Dose Escalation only)
v) Tumor cell PD-L1 expression status by local or central testing must be available prior to randomization (Part 2 Dose Expansion only).
3) Physical and laboratory test findings
a) Any toxicity from previous antitumor therapy must have returned to baseline or Grade ≤ 1 as defined by NCI-CTCAE v5.0 (except for asymptomatic laboratory abnormalities and except for any toxicity that the investigator determined to have no safety risk, for example: alopecia) Participants must have adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 45% as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
b) Participants must have adequate bone marrow reserve and organ function based on local laboratory data:
i) Peripheral blood absolute neutrophil count (ANC) ≥ 1.5 × 109/L (granulocyte colony stimulating factor support is not allowed within 14 days prior to the assessment during the screening period)
ii) Platelet count ≥ 100 × 109/L (platelet transfusions are not allowed within 14 days prior to the assessment of platelets during the screening period)
iii) Hemoglobin (Hb) ≥ 90 g/L (transfusion of red blood cells and/or growth factor support is not allowed within 14 days prior to the assessment during the screening period)
iv) Total bilirubin ≤ 1.5× ULN, if no liver metastases. In the presence of documented Gilbert’s syndrome [unconjugated hyperbilirubinemia] or liver metastases < 3× ULN.
v) AST and ALT without liver metastasis ≤ 2.5× ULN, AST and ALT with liver metastasis ≤ 5.0× ULN
vi) Creatinine clearance (CrCl): CrCl ≥ 50 mL/min, as calculated using the Cockcroft-Gault equation.
vii) International normalized ratio (INR) ≤ 1.5× ULN, and activated partial thromboplastin time (APTT) ≤ 1.5× ULN
viii) Urinary protein ≤ 2+ or ≤ 1000 mg/24 hours
4) Age of Participant
a) Participant must be at least 18 years of age at the time of signing the ICF.
5) Reproductive Status
The investigator or designee shall counsel individuals of childbearing potential (IOCBP) participants (as defined in Appendix 4) and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to
transmission of study intervention present in seminal fluid to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
Local laws and regulations may require the use of alternative and/or additional contraceptive methods.
a) Female (as assigned at birth) participants:
i) Female (as assigned at birth) participants who are not of childbearing potential must have documented proof. Note: Documentation can be obtained from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.
Individuals who are not of childbearing potential (as defined in Appendix 4) are exempt from contraceptive requirements.
ii) IOCBP must have a negative highly sensitive urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study intervention.
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are in Section 2.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy.
iii) IOCBP and male (as assigned at birth) participants who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.
IOCBP are permitted to use hormonal contraceptive methods (as described in Appendix 4).
iv) A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies:
Is not an IOCBP OR
Is an IOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with user independent methods as described in Appendix 4, during the intervention period and for at least 7 months after the last dose of BMS-986507. IOCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction and not to breastfeed for the same period.
b) Male (as assigned at birth) participants:
i) Males (as assigned at birth) who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.
(1) Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
(2) Male participants are required to use a condom during the intervention period and for at least 7 months after the last dose of BMS-986507.
(3) IOCBP partners of male participants should be advised to use a highly effective method of contraception during the study intervention period and for at least 7 months after the last dose of BMS-986507.
(4) Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral) during the intervention period and for at least 7 months after the last dose of BMS-986507.
(5) Male participants must refrain from donating sperm during the intervention period and for at least 7 months after the last dose of BMS-986507.
(6) Breastfeeding partners of male participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms.
Exclusion Criteria
1) Medical Conditions
a) Mixed SCLC and NSCLC histology
b) Participants with known mutations and/or translocations in the following genes will be excluded: EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, RET, HER2 and KRAS (Group B only)
c) Untreated symptomatic central nervous system (CNS) metastases. Participants are eligible if CNS metastases have been treated and do not require immediate treatment or have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment). In addition, participants must have been either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to treatment assignment. Imaging performed within 28 days prior to treatment assignment must document radiographic stability of CNS lesions and be performed after completion of any CNS directed therapy.
d) Leptomeningeal metastases.
e) Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to treatment assignment (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before treatment assignment and the participant has no evidence of disease). Participants with history of prior early-stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
f) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of treatment assignment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
g) Participants with Grade 3 lung disease defined according to NCI-CTCAE v5.0, or a history of interstitial lung disease (ILD) or pneumonitis (previous Grade 1 or 2 pneumonitis is permitted if completely resolved)
h) Participants with history of serious recurrent infections
i) Participants with active autoimmune diseases and inflammatory diseases, such as: systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease and Hashimoto’s thyroiditis, etc. Participants with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
j) Participants with history of ≥ Grade 3 toxicity related to prior T cell agonist or checkpoint inhibitor therapy (eg, anti CTLA-4, anti-PD-1/PD-L1 treatment, or any other antibody or drug specifically targeting T cell co-stimulation or other immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after adrenal crisis) (Group B only)
k) Participants with history of severe heart disease including, but not limited to, any of the following:
i) Myocardial infarction or stroke/transient ischemic attack within the past 12 months.
ii) Uncontrolled angina within the past 3 months.
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes).
iv) History of other clinically significant heart disease (eg, cardiomyopathy, congestive heart failure with New York Heart Association functional classification III to IV, pericarditis, or significant pericardial effusion).
v) Cardiovascular disease-related requirement for daily supplemental oxygen therapy.
vi) QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation > 470 msec, except for right bundle branch block.
vii) History of myocarditis, regardless of etiology.
l) Participants with poorly controlled hypertension by 2 kinds of antihypertensive drugs (systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg)
m) Participants with known bleeding coagulation disorders, including but not limited to hemophilia, von Willebrand disease, or any other coagulopathies that may affect blood clotting.
n) Participants who have a history of autologous or allogeneic stem cell transplantation (Allo- HSCT)
o) Participants with active infections requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc, ≤ 7 days prior to the first dose of study treatment.
p) Participants with positive hepatitis B surface antigen (HBsAg) unless hepatitis B virus (HBV) DNA < 500 IU/mL and participant is taking antiviral therapy.
q) Participants with positive hepatitis C virus (HCV) antibody unless HCV‑RNA is undetectable.
r) Participants are taking antiviral therapy for HCV. (Note: Participants who have completed antiviral therapy for HCV and who have undetectable levels of HCV-RNA are allowed.)
s) Participant has active co-infection (Hep B and Hep C) or (Hep B and Hep D).
t) Participant has known human immunodeficiency virus (HIV) positive with an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the last year or a current CD4 count < 350 cells/uL. Participants with HIV are eligible if:
Participant has received antiretroviral therapy (ART) for at least 4 weeks and have an HIV viral load of < 400 copies/ML prior to enrollment prior to Choose: randomization/treatment assignment as clinically indicated while enrolled on study.
Participant are not reiceiving ART with strong CYP3A4 inhibitors (refer to Section 7.7.1).
Participant continues ART as clinically indicated while enrolled on study.
Participant’s CD4 counts and viral load are monitored per SoC by a local health care provider.
(Note: Testing for HIV must be performed at sites. HIV-positive participants must be excluded where mandated locally).
u) Toxicity (except for alopecia) related to prior anticancer therapy and/or surgery, unless the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.
v) Participants with any condition, including active or uncontrolled infection, or the presence of laboratory abnormalities, that places the participant at unacceptable risk if he/she were to participate in the study or interfere with study intervention or follow-up.
w) Any known or underlying medical or psychiatric condition and/or social reason that, in the opinion of the Investigator or Sponsor, could make the administration of study intervention hazardous to the participant or could adversely affect the ability of the participant to comply with or tolerate the study.
x) Current or recent (within 3 months of study drug administration) gastrointestinal disease or gastrointestinal surgery (eg, intestinal/gastric/colon resection) that could impact the absorption of the study drug (Group A only)
2) Reproductive Status
a) Individuals who are breastfeeding
b) Individuals who are pregnant
3) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7:
Concomitant Therapy.
b) Past or intended use of over-the-counter or prescription medication [including herbal medications] within 14 days prior to dosing. Permitted and prohibited medications are listed in Section 7.7.
c) Participants who have received prior treatment with any systemic anticancer therapy for locally advanced/metastatic NSCLC (except Group B, Part 1 Dose Escalation)
d) Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, major surgery, targeted therapy (including small molecule inhibitor of tyrosine kinase), and other antitumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration; oral fluorouracil-like drugs such as S-1, capecitabine, or palliative radiotherapy within 2 weeks prior to the first administration.
e) Participants receiving strong inhibitors and/or inducers of CYP1A2, CYP2C9, and CYP3A4 and/or BCRP inhibitors.
f) Participants who have received strong inhibitors and/or inducers of CYP1A2, CYP2C9, and CYP3A4 and/or BCRP inhibitors within 2 weeks prior to the first dose of the study treatment.
g) Participants who are currently receiving treatment with any medications that have the potential to prolong the QT interval if that treatment cannot be either discontinued or switched to a different medication prior to administration of study drug (Group A only)
h) Participation in a study of an investigational agent and received study therapy or used an investigational device within 28 days or 5 half-lives (whichever is shorter).
i) Treatment with any live/attenuated vaccine within 30 days of first study treatment
j) Previous SARS-CoV-2 vaccine within 7 days of C1D1. For vaccines requiring more than 1 dose, the full series (eg, both doses of a 2-dose series) should be completed prior to C1D1 when feasible and when a delay in C1D1 would not put the study participant at risk.
k) Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior C1D1.
l) Prior therapy with BMS-986507 or any other ADC targeting EGFR and/or HER3 or containing topoisomerase 1 inhibitor as payload, is not permitted
4) Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population.
b) Participants with low concentration of potassium in the blood that are above Grade 1 according to NCI-CTCAE v5.0 (Grade 1: participant asymptomatic with potassium levels < LLN – 3.0 mmol/L or equivalent)
5) Allergies and Adverse Drug Reactions
a) Participants who have a history of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
b) Participants who have a history of allergies or hypersensitivity to any of the components (including excipients) of BMS-986507
c) Participants who have a history of allergies to recombinant humanized antibodies or human mouse chimeric antibodies (Group B only)
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply, and Sponsor approval is required.)
b) Inability to comply with restrictions as listed in Section 6.3 Lifestyle Restrictions
c) Participation in another clinical trial concurrent with this study
d) Any significant acute or chronic medical illness
e) Any major surgery within 4 weeks of study intervention administration
