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Dostarlimab Alone or in Combination with Cobolimab for the Treatment of Resectable Stage III or IV Melanoma

Trial Status: Active

This phase II trial investigates how well dostarlimab alone or in combination with cobolimab works in treating patients with stage III or stage IV melanoma that can be removed by surgery (resectable). Dostarlimab is a PD-1 inhibitor and cobolimab is a TIM-3 inhibitor. Dostarlimab works by encouraging the body’s own immune system to attack the cancer cells. The immune system is a network of cells, tissues, and organs that work together to defend the body against diseases. Cobolimab may improve upon the benefit of dostarlimab. Giving dostarlimab in combination with cobolimab may work better to treat stage III or IV melanoma compared to dostarlimab alone.

Inclusion Criteria

  • Be willing and able to provide written informed consent for the study
  • Diagnosis of histologically or cytologically confirmed diagnosis of cutaneous or unknown primary melanoma (excluding uveal/choroidal and mucosal melanoma; although acral melanoma is included) belonging to one of the following American Joint Committee on Cancer (AJCC) 8th edition TNM stages: * Tx or T1-4 AND * N1b, or N1c, or N2b, or N2c, or N3b, or N3c AND/OR * M1a
  • Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or oligometastasis; AND/OR at the time of clinical detected nodal and/or in transit and/or oligometastatic recurrence; and may belong to any of the following groups: * Primary melanoma with clinically apparent regional lymph node metastases (deemed resectable) * Clinically detected recurrent melanoma at the proximal regional lymph node(s) basin (deemed resectable) * Clinically detected primary melanoma involving multiple regional nodal groups (deemed resectable) * Clinical detected nodal melanoma (if single site) arising from an unknown primary (deemed resectable) * In-transit and/or satellite metastases with or without regional lymph node involved permitted if deemed resectable at baseline * Distant skin and/or in-transit and/or satellite metastases with or without regional lymph node involved permitted if deemed resectable at baseline ** The site/number of resectable lesions should be recorded on the initial case report form * NOTE: Determination of resectability must be made at baseline to be eligible for this neoadjuvant study
  • Presence of measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Have provided tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy. Patients must undergo biopsy (core, punch) or open biopsy (incisional, excisional) within 4 weeks of registration on the study
  • Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500 /mcL (obtained within 14 days of registration)
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (obtained within 14 days of registration)
  • Platelets >= 100,000 / mcL (obtained within 14 days of registration)
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels >1.5 x institutional ULN (obtained within 14 days of registration)
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (obtained within 14 days of registration)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN (obtained within 14 days of registration)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (obtained within 14 days of registration)
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (obtained within 14 days of registration)
  • Female subject of childbearing potential should have a negative serum pregnancy test within 1 week prior to receiving the first dose of study medication and use an adequate method of contraception starting with the first dose of study therapy through 26 weeks after the last dose of study therapy. Non-childbearing potential is defined as follows (by other than medical reasons): * >= 45 years of age and has not had menses for > 1 year * Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use an adequate method of contraception throughout the study and for 26 weeks after the last dose of study therapy ** Note: Abstinence is acceptable if this is the established and preferred contraception for the patient
  • Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 26 weeks after the last dose of study therapy

Exclusion Criteria

  • Patients with uveal and/or mucosal melanoma histology are excluded * Patients with melanoma of unknown histology are permitted to enroll after discussion with principal investigator
  • Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
  • Is receiving systemic immunosuppression with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications for active autoimmune disease * Note: Patients with a history of active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids (> 10 mg daily prednisone or equivalent) or systemic immunosuppressive agents are excluded * Note: Subjects with vitiligo or resolved childhood asthma/atopy or those with inactive/minimally active disease who have received clearance from a consultant rheumatologist to participate are exceptions to this rule * Note: Subjects that require intermittent use of bronchodilators or local steroid injections are not to be excluded from the study
  • Has experienced >= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 immune-related adverse event (irAE) with prior immunotherapy, with the following exceptions * Subjects who developed non-clinically significant lab abnormalities (elevations in lipase, amylase not associated with clinically significant disease etc.) even if >= CTCAE grade 3 may enroll if resolved at this time * Subjects who developed autoimmune disorders of grade =< 3 may enroll if the disorder has resolved to grade =< 1 * Note: Subjects who require steroids for autoimmune (or other) disorders are permitted to enroll if steroids requirements are =< prednisone 10 mg daily (or equivalent) * Note: Subjects whose irAEs have resolved or are well controlled (i.e.: hypothyroidism stable on hormone replacement etc) are permitted to enroll
  • Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received surgery, they must have recovered adequately from complications prior to starting therapy * Note: Subjects with autoimmune disorders of grade 4 while on prior immunotherapy will be excluded
  • Has active (i.e., symptomatic or growing) central nervous system (CNS) and/or leptomeningeal metastases * Note: Patients with CNS lesions that are treated and deemed stable (repeat imaging study done at least 2 weeks prior to first dose of study treatment) are NOT permitted to enroll even if other inclusion criteria are met and patients are neurologically asymptomatic
  • Has a known additional malignancy that is progressing or requires active treatment * Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy * Note: Patients with invasive cancer diagnosed and treated greater than 2 years prior to current presentation can be enrolled * Note: Patients with other indolent malignancies that are not progressing and/or deemed to require active therapy may enroll if other inclusion criteria are met
  • Has evidence of interstitial lung disease or active, non-infectious pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome)
  • 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 trial, starting with the pre-screening or screening visit through 26 weeks after the last dose of trial treatment
  • Has a live vaccine within 30 days of initiating protocol therapy
  • Has received prior therapy with an IDO inhibitor, anti-PD-1, anti-PD-L1, anti-PD-L2, antiC-D137 and/or combination (including nivolumab, pembrolizumab or ipilimumab/nivolumab) * Note: Prior treatment with ipilimumab or interferon alfa is allowed * Note: Patients with history of allergic or hypersensitivity reaction to components or excipients of dostarlimab (TSR-042) and TSR-022, interferon alfa or ipilimumab are also excluded
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known history of or screening test that is positive for hepatitis B virus (HBV; e.g., hepatitis B surface antigen [HBsAg] reactive or HBV deoxyribonucleic acid [DNA] detected) or hepatitis C virus (HCV; HCV antibody positive and/or HCV ribonucleic acid [RNA] quantitative is detected) * Note: Hepatitis C antibody–positive subjects who received and completed treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable * Note: Hepatitis B positive subjects who received and completed treatment for hepatitis B that was intended to eradicate the virus may participate if hepatitis B DNA levels are undetectable

Pennsylvania

Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: ACTIVE
Contact: Diwakar Davar
Phone: 412-623-7368

PRIMARY OBJECTIVE:

I. To evaluate major pathologic response rate (MPR rate) in patients with stage III B/C/D or stage IV A melanoma treated with either 6 weeks of dostarlimab (TSR-042) compared to 6 weeks of dostarlimab (TSR-042)/cobolimab (TSR-022) combination.

SECONDARY OBJECTIVE:

I. To evaluate safety, frequency of delay/cancellation in surgery, relapse-free survival (RFS) and overall survival (OS) in patients with stage III B/C/D or stage IV A melanoma following neoadjuvant/adjuvant therapy.

EXPLORATORY OBJECTIVES:

I. To evaluate circulating and intra-tumoral immune cells, including T-cells (CD8, CD4, regulatory T cells [Tregs]) and antigen-presenting cells (monocytes, macrophages, myeloid-derived suppressor cells [MDSCs]), for the expression of inhibitory and activating receptors and ligands including functional analyses.

II. To evaluate T-cell receptor (TCR) clonality/diversity analyses of circulating and intra-tumoral CD8+ T-cells before and after dostarlimab (TSR-042) and TSR-022 administration.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I:

PRE-OPERATIVE PHASE: Patients receive dostarlimab intravenously (IV) over 30 minutes on day 1 of each cycle for cycles 1-2. Treatment repeats every 3 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning 1-4 weeks later, patients undergo surgery.

POST-OPERATIVE PHASE: Patients receive dostarlimab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 2 cycles and then every 6 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM II:

PRE-OPERATIVE PHASE: Patients receive dostarlimab IV over 30 minutes on day 1 and cobolimab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning 1-4 weeks later, patients undergo surgery.

POST-OPERATIVE PHASE: Patients receive dostarlimab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 2 cycles and then every 6 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for up to 15 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Pittsburgh Cancer Institute (UPCI)

Principal Investigator
Diwakar Davar

  • Primary ID HCC 19-047
  • Secondary IDs NCI-2020-05492
  • Clinicaltrials.gov ID NCT04139902