Inclusion Criteria:
- - Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed diagnosis of cutaneous melanoma (or
unknown primary) will be enrolled in this study.
- - Male participants: A male participant must agree to use a contraception during the
treatment period and for at least 120 days after the last dose of study treatment and
refrain from donating sperm during this period.
- - Female participants: A female participant is eligible to participate if she is not
pregnant, not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP); OR.
- - A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for at least 120 days after the last dose of study treatment.
- - Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered
either as monotherapy or in combination with other checkpoint inhibitors or other
therapies.
PD-1 treatment progression is defined by meeting all of the following
criteria:
- - Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
- - Participants who progressed on/within 3 months of adjuvant therapy with
anti-PD-(L)1 inhibitor will be allowed.
- - Has demonstrated disease progression after anti-PD-1/L1 as defined by RECIST
v1.1.
The initial evidence of PD is to be confirmed by a second assessment no
less than 4 weeks from the date of the first documented PD, in the absence of
rapid clinical progression (as defined in 4.c).
- - Progressive disease has been documented within 12 weeks from the last dose of
anti-PD-1/L1 mAb.
- - Progressive disease as determined above.
This determination is made by the
treating investigator. Once PD is confirmed, the initial date of PD documentation
will be considered the date of PD. Anti-PD/L1 mAb need not be the most recent
line of therapy administered.
- - Prior treatment with an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
antibody is allowed but not required.
- - Prior treatment with BRAF/MEK inhibitor therapy (if BRAF mutated) is allowed but not
required.
- - The participant provides written informed consent for the trial.
- - Presence of measurable disease based on RECIST 1.1.
- - Patients need to have at least one measurable lesion and a separate lesion for
biopsy.
Patients with only 1 lesion may be enrolled after discussion with
Sponsor-Investigator.
- - Lesions situated in a previously irradiated area are considered measurable if
progression has been demonstrated in such lesions.
- - Able to provide newly obtained core or excisional biopsy of a tumor lesion not
previously irradiated to undergo tumor biopsy (core, punch, incisional or excisional).
--- Biopsy must meet minimal sampling criteria.
- - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed at screening prior to the first dose of study
intervention.
- - Have adequate organ function as defined below.
Specimens must be collected within 28
days prior to the start of study intervention.
- - Absolute neutrophil count (ANC) ≥1500/µL.
- - Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietin
dependency and without packed red blood cell (pRBC) transfusion within last 2
weeks)
- Creatinine OR Measured or calculated creatinine clearance (GFR can also be used
in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with
creatinine levels >1.5 × institutional ULN (Creatinine clearance (CrCl) should be
calculated per institutional standard)
- Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 × ULN.
- - AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver
metastases)
- International normalized ratio (INR) OR prothrombin time (PT) and Activated
partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as PT or aPTT is within therapeutic range of
intended use of anticoagulants.
Exclusion Criteria:
- - Receipt of prior agent(s) targeting components of the TIGIT/CD226 pathway including
but not limited to CD226, TIGIT, PVR/CD155 and CD112.
- - Diagnosis of non-cutaneous melanoma histologies including mucosal melanoma,
ocular/choroidal melanoma, acral-lentiginous melanoma.
- - Diagnosis of immunodeficiency, immunosuppression and/or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of trial treatment.
- - Prior chemotherapy, targeted therapy, and/or small molecule therapy within 2 weeks (or
4 half lives) prior to study Day 1.
- - Patients who have not recovered (i.e., ≤Grade 1 or at baseline or ≤Grade 2
endocrinopathy) from adverse events (AEs) due to a previously administered agent.
- - Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis.
--- A 2-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy)
to non-CNS disease.
- - A WOCBP who has a positive urine pregnancy test at Screening.
If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- - Has received a live vaccine within 30 days prior to the first dose of study drug.
- - Examples of live vaccines include, but are not limited to, the following:
measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,
Bacillus Calmette-Guérin (BCG), and typhoid vaccine.
- - Seasonal influenza vaccines for injection are generally killed virus vaccines and
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live
attenuated vaccines and are not allowed.
- - Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 14 days prior to the first dose of study drug.
- - Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs).
--- Note: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment and is allowed.
- - Concurrent non-hematologic malignancy within 3 years of data of first planned dose of
therapy except for tumors with a negligible risk of metastasis and/or death as defined
below:
- Adequately treated non-invasive malignancies including but not limited to
melanoma in situ (MIS), cutaneous squamous cell carcinoma (cSCC), in situ cSCC,
basal cell carcinoma (BCC), CIS of cervix, or DCIS/LCIS of breast.
- - Low-risk early-stage prostate adenocarcinoma (T1-T2a N0 M0 and Gleason score ≤6
and PSA ≤10 ng/mL) for which the management plan is active surveillance, or
prostate adenocarcinoma with biochemical-only recurrence with documented PSA
doubling time of > 12 months for which the management plan is active
surveillance.
- - Indolent hematologic malignancies for which the management plan is active
surveillance including but not limited to CLL/indolent lymphoma.
Patients with
high-risk hematologic malignancies (CML, ALL, AML, Hodgkin's or non-Hodgkin's
lymphoma) are excluded even if the management plan is active surveillance.
- - Active (i.e., symptomatic or growing) central nervous system (CNS) metastases.
- - Note: Participants with previously treated brain metastases may participate
provided they are radiologically stable, i.e. without evidence of progression for
at least 4 weeks by repeat imaging (note that the repeat imaging should be
performed during Screening), clinically stable and without requirement of steroid
treatment for at least 14 days prior to first dose of study intervention.
- - Patients with leptomeningeal disease are excluded.
- - Has severe hypersensitivity (≥Grade 3) to anti-PD(L)1 inhibitor.
- - Has a systemic disease that requires systemic pharmacologic doses of corticosteroids
greater than 10 mg daily prednisone (or equivalent).
- - Note: Participants who are currently receiving steroids at a dose of ≤10 mg daily
do not need to discontinue steroids prior to enrollment.
- - Note: Participants that require topical, ophthalmologic, injected and/or
inhalational steroids are not excluded from the study.
- - Note: Participants with hypothyroidism stable on hormone replacement or Sjogren's
syndrome are not excluded from the study.
- - Note: Participants who require active immunosuppression (greater than steroid
dose discussed above) for any reason are excluded from the study.
- - Has a history of interstitial lung disease or active, non-infectious pneumonitis that
required steroids or has current pneumonitis.
- - Has an active infection requiring systemic therapy.
- - Has a known history of Human Immunodeficiency Virus (HIV) infection.
- - Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) and/or known active Hepatitis C virus (defined as anti-HCV reactive)
infection.
- - Patients with treated Hepatitis B/C with no evidence of active infection may be
enrolled.
- - Patients with a history of Hepatitis B and/or C who have been treated with
curative intent may be enrolled if there is no evidence of active infection
(Hepatitis B: negative HBsAg, Hepatitis C: undetectable HCV viral load)
- Has a known history of active TB (Bacillus Tuberculosis).
- - Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
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.
- - Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- - Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the Screening visit through 120 days
after the last dose of trial treatment.
- - Has had an allogenic tissue/solid organ transplant.
