| Eligibility |
Inclusion Criteria:
To participate in the study, participants must meet all the following inclusion criteria:
Cohort A only:
1. Prior treatment with anti-PD-(L)1 therapy (for example, pembrolizumab or nivolumab)
for at least 6 weeks and radiologic progression confirmed by 2 scans at least 4 weeks
apart, or if symptomatic due to progressive malignancy, then 1 scan showing
progression is sufficient.
2. Progression must be either on treatment with anti-PD-(L)1 regimen or = 12 weeks from
last anti-PD-(L)1 dose in metastatic setting or = 24 weeks from completion of therapy
in adjuvant/ neoadjuvant setting.
3. For Part 2 only, no intervening anti-cancer therapy between the last course of
anti-PD-(L)1 treatment and the first dose of study treatment except for local measures
(for example, surgical excision, biopsy, focal radiation therapy), or BRAF ± MEK
inhibition when applicable in BRAF mutant participants.
Cohort B only:
1. Prior treatment with first-generation anti-CTLA-4 therapy (for example, ipilimumab or
tremelimumab) and prior treatment with anti-PD-(L)1 for at least 6 weeks.
2. Progression on most recent anti-neoplastic therapy.
3. For Part 2 only, no more than 3 prior lines of therapy in the advanced setting for
BRAF mutant and no more than 2 prior lines of therapy in the advanced setting in the
BRAF wild type.
Cohorts A and B:
1. Voluntarily agree to participate by giving signed, dated, and written informed consent
prior to any study-specific procedures.
2. Histological confirmation of Stage III (unresectable) or Stage IV cutaneous melanoma,
per the American Joint Committee on Cancer 8th edition staging system.
3. Measurable disease on baseline imaging per RECIST 1.1 criteria.
4. BRAF V600 mutation status or consent to BRAF V600 mutation testing per local
institutional standards during the screening period.
5. Life expectancy = 3 months.
6. Eastern Cooperative Oncology Group performance status of 0 or 1.
7. Adequate organ function is defined as the following laboratory values within 21 days
of Cycle 1 Day 1 (C1D1):
1. Neutrophils > 1500/microliter (µL) (stable off any growth factor within 4 weeks
of first study treatment administration).
2. Platelets > 100 × 10^3/µL (transfusion to achieve this level is not permitted
within 2 weeks of first study treatment administration).
3. Hemoglobin > 8.0 grams/deciliter (g/dL) (transfusion to achieve this level is not
permitted within 2 weeks of first study treatment administration).
4. Creatinine clearance = 45 milliliters/minute (measured or calculated using
modification of diet in renal disease).
5. Aspartate aminotransferase/alanine aminotransferase < 3.0 × upper limit of normal
(ULN).
6. Total bilirubin < 1.5 × ULN, or < 3.0 × ULN for participants with Gilbert
syndrome.
7. Albumin = 3.0 g/dL.
8. International normalized ratio or prothrombin time = 1.5 × ULN and activated
partial thromboplastin time = 1.5 × ULN (unless participant is receiving
anticoagulant therapy).
8. Participant must provide a formalin-fixed paraffin-embedded tumor tissue sample from
the most recent biopsy of a tumor lesion, obtained within 90 days from signing
informed consent form. If recent tumor tissue is unavailable or inadequate, a fresh
biopsy will be required, unless the Sponsor agrees that it is not safe/feasible.
9. Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy
test at screening (within 72 hours of first dose of study medication) and prior to
study drug administration. In part 1, WOCBP must agree to use highly effective
contraceptive measures starting with the screening visit through 3 months after the
last dose of study treatment. In Part 2, WOCBP must agree to use highly effective
contraceptive measures starting with the screening visit through 5 months after the
last dose of study treatment. Note: Abstinence is acceptable if this is the
established and preferred contraception for the participant.
10. In Part 1, male participants with a female partner(s) of childbearing potential must
agree to use highly effective contraceptive measures throughout the study, starting
with the screening visit through 3 months after the last dose of study treatment is
received. In Part 2, male participants with a female partner(s) of childbearing
potential must agree to use highly effective contraceptive measures throughout the
study starting with the screening visit through 5 months after the last dose of study
treatment is received. Males with pregnant partners must agree to use a condom; no
additional method of contraception is required for the pregnant partner.
Exclusion Criteria:
To participate in the study, participants must meet none of the following exclusion
criteria:
Cohort A:
1. Received prior anti-CTLA-4 therapy.
Cohort B:
1. Received prior Fc-engineered or Fc-enhanced anti-CTLA-4 therapy (for example, BMS-96218,
BMS-986288, HBM4003, XTX101, CTLA-4 targeting bispecific or other approaches such as
ONC-392).
Cohorts A and B:
1. Ocular, uveal, or mucosal melanoma.
2. Any persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE]
Grade = 2) from prior cancer therapy, excluding endocrinopathies stable on medication,
stable neuropathy, and alopecia.
3. Any history of CTCAE Grade = 3 immune-mediated toxicity (excluding endocrinopathies
and non-necrotizing/bullous rash) from prior checkpoint inhibition.
4. Refractory ascites require 2 or more therapeutic paracentesis in the last 4 weeks or =
4 within the last 90 days prior to study entry.
5. Bowel obstruction within the past 3 months or an impending bowel obstruction.
6. Clinically significant (that is, active) cardiovascular disease: cerebral vascular
accident/stroke or myocardial infarction within 6 months of enrollment, unstable
angina, congestive heart failure (New York Heart Association class = III), or serious
uncontrolled cardiac arrhythmia requiring medication.
7. Active brain metastases or leptomeningeal metastases with the following exceptions:
1. Treated brain metastases require a) surgical resection, or b) stereotactic
radiosurgery. These participants must be off steroids = 10 days prior to
randomization for the purpose of managing their brain metastases. Repeat brain
imaging following surgical resection or stereotactic radiosurgery is not required
if their last brain magnetic resonance imaging is within screening window.
Whole-brain radiation is not allowed.
2. Untreated isolated brain metastases that are too small for treatment by surgical
resection or stereotactic radiosurgery (for example, 1-2 millimeters) and/or of
uncertain etiology are potentially eligible but need to be discussed with and
approved by the study Medical Monitor.
8. Concurrent malignancy (present during screening) requiring treatment or history of
prior malignancy active within 2 years prior to the first dose of study treatment
(that is, participants with a history of prior malignancy are eligible if treatment
was completed at least 2 years before the first dose of study treatment and the
participant has no evidence of disease). Participants with history of prior
early-stage basal/squamous cell skin cancer, low-risk prostate cancer eligible for
active surveillance or noninvasive or in situ cancers who have undergone definitive
treatment at any time are also eligible.
9. Incomplete resolution of clinically significant adverse events related to most recent
therapy/intervention prior to enrollment.
10. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine or booster < 7
days before C1D1. For vaccines requiring more than 1 dose, the full series should be
completed prior to C1D1, when feasible. A booster shot is not required but also must
be administered > 7 days from C1D1 or > 7 days from future cycle on study.
11. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
12. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior
history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
13. History of allogeneic organ transplant.
14. Psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the study.
15. Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 milligrams [mg] daily prednisone equivalent) within 14 days or another
immunosuppressive medication within 30 days of the first dose of study treatment.
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily
prednisone equivalent, are permitted in the absence of active autoimmune disease.
16. Active autoimmune disease or history of autoimmune disease that required systemic
treatment within 2 years before starting study treatment (that is, with use of
disease-modifying agents or immunosuppressive drugs).
17. History or current evidence of any condition, co-morbidity, therapy, any active
infections, or laboratory abnormality that might confound the results of the study,
interfere with the participants participation for the full duration of the study, or
is not in the best interest of the participant to participate, in the opinion of the
treating Investigator.
18. A WOCBP who is pregnant or breastfeeding or WOCBP who are not willing to employ
effective birth control from screening to 90 days after the last dose of botensilimab
(whichever is later).
19. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20
days for severe/critical illness prior to C1D1.
20. Uncontrolled infection with human immunodeficiency virus (HIV). Participants on stable
highly active antiretroviral therapy with undetectable viral load and normal cluster
of differentiation 4 counts for at least 6 months prior to study entry are eligible.
Serological testing for HIV at screening is not required.
21. Known to be positive for hepatitis B virus (HBV) surface antigen, or any other
positive test for HBV indicating acute or chronic infection. Participants who are
receiving or who have received anti-HBV therapy and have undetectable HBV DNA for at
least 6 months prior to study entry are eligible. Serological testing for HBV at
screening is not required.
22. Known active hepatitis C virus (HCV) as determined by positive serology and confirmed
by polymerase chain reaction (PCR). Participants on or who have received
antiretroviral therapy are eligible, provided they are virus-free by PCR for at least
6 months prior to study entry. Serological testing for HCV at screening is not
required.
23. Dependence on total parenteral nutrition.
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