Clinical Trials /

PD-1 Inhibitor Dostarlimab (TSR-042) vs. Combination of Tim-3 Inhibitor TSR-022 and PD-1 Inhibitor Dostarlimab (TSR-042)

NCT04139902

Description:

The purpose of this study is to test the effects of anti-PI-1 inhibitor (TSR-042) or anti-PD-1/anti-TIM-3 combination (TSR-042 / TSR-022) in patients with operable melanoma.

Related Conditions:
  • Cutaneous Melanoma
  • Melanoma of Unknown Primary
  • Mucosal Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PD-1 Inhibitor Dostarlimab (TSR-042) vs. Combination of Tim-3 Inhibitor TSR-022 and PD-1 Inhibitor Dostarlimab (TSR-042)
  • Official Title: Randomized Phase II Neoadjuvant Study of PD-1 Inhibitor Dostarlimab (TSR-042) vs. Combination of Tim-3 Inhibitor TSR-022 and PD-1 Inhibitor Dostarlimab (TSR-042) in Resectable Stage III or Oligometastatic Stage IV Melanoma (Neo-MEL-T)

Clinical Trial IDs

  • ORG STUDY ID: 19-047
  • NCT ID: NCT04139902

Conditions

  • Melanoma Stage III
  • Melanoma Stage IV

Interventions

DrugSynonymsArms
Dostarlimab (TSR-042) (singly)DostarlimabDostarlimab (TSR-042) (singly)
Dostarlimab (TSR-042) and TSR-022 (combination)Dostarlimab (TSR-042) and TSR-022 (combination)

Purpose

The purpose of this study is to test the effects of anti-PI-1 inhibitor (TSR-042) or anti-PD-1/anti-TIM-3 combination (TSR-042 / TSR-022) in patients with operable melanoma.

Detailed Description

      This is a randomized phase II neoadjuvant study comparing neoadjuvant therapy with PD-1
      inhibitor Dostarlimab (TSR-042) to the PD-1/TIM-3 inhibitor combination Dostarlimab
      (TSR-042)/TSR-022 in patients with resectable regionally advanced or oligometastatic
      melanoma.

      Patients with stage III B/C/D or oligometastatic stage IV A melanoma with lymph node (LN)
      and/or in-transit and/or oligometastatic disease who have yet to undergo definitive surgery
      are eligible to enroll.

      Suitable patients will be identified pre-operatively. Patients will undergo screening
      evaluation consisting of systemic/CNS staging scans, tumor biopsy, blood studies to confirm
      suitability. Subjects will receive neoadjuvant therapy (Dostarlimab (TSR-042) or Dostarlimab
      (TSR-042)/TSR-022 combination for 6 weeks prior to planned surgery (pre-operative phase).
      Surgery will occur 1-4 weeks after completion of pre-operative therapy. After recovery from
      surgery subjects will receive Dostarlimab (TSR-042) (maintenance phase) for approximately 48
      weeks; for a total of 54 weeks of study drug(s) administration in total.
    

Trial Arms

NameTypeDescriptionInterventions
Dostarlimab (TSR-042) (singly)ExperimentalPre-operative Phase: Dostarlimab (TSR-042) 500mg will be administered through an IV over 30 minutes, on Cycle 1 Day 1, and then again on Cycle 2 Day 1. Post-operative Phase: Dostarlimab (TSR-042) 500mg will be administered through an IV over 30 minutes for 4 cycles every 3 weeks (Cycles 3-4) and then 1000mg will be administered through an IV over 30 minutes every 6 weeks (Cycles 5-10) for approximately 48 weeks.
  • Dostarlimab (TSR-042) (singly)
Dostarlimab (TSR-042) and TSR-022 (combination)ExperimentalPre-operative Phase: Dostarlimab (TSR-042) 500mg and TSR-022 900mg will be administered through an IV over 30 minutes, on Cycle 1 Day 1 and then again on Cycle 2 Day 1. Post-operative Phase: Dostarlimab (TSR-042) will be administered through an IV over 30 minutes for 4 cycles every 3 weeks (Cycles 3-4), and then 1000mg will be administered through an IV over 30 minutes every 6 weeks (Cycles 5-10) for approximately 48 weeks. TSR-022 will not be administered.
  • Dostarlimab (TSR-042) and TSR-022 (combination)

Eligibility Criteria

        Inclusion Criteria:

          -  written informed consent for the study

          -  ≥ 18 years of age

          -  histologically or cytologically confirmed diagnosis of cutaneous or mucosal or unknown
             primary melanoma (excluding uveal/choroidal melanoma; acral melanoma is included)
             belonging to one of the following AJCC 8th edition TNM stages:

               1. Tx or T1-4 AND

               2. N1b, or N1c, or N2b, or N2c, or N3b, or N3c AND/OR

               3. M1a, or M1b

          -  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 (resectability
             determination/deemed resectable at baseline to be eligible), includes: Primary
             melanoma with clinically apparent regional lymph node metastases; Clinically detected
             recurrent melanoma at the proximal regional lymph node(s) basin; Clinically detected
             primary melanoma involving multiple regional nodal groups; Clinical detected nodal
             melanoma (if single site) arising from an unknown primary; In-transit and/or satellite
             metastases with or without regional lymph node involvement; Distant skin and/or
             in-transit and/or satellite metastases with or without regional lymph node involvement

          -  measurable disease based on RECIST 1.1

          -  must provide tumor tissue from a newly obtained core, punch, incisional or excisional
             tumor biopsy

          -  0 or 1 on the ECOG Performance Scale

          -  Demonstrate adequate organ function on screening labs obtained within 14 days of
             registration

          -  negative serum pregnancy test (females of childbearing potential)

          -  females of non-childbearing potential must be ≥45 years of age and has not had menses
             for >1 year; if amenorrhoeic for <2 years without history of a hysterectomy and
             oophorectomy must have an FSH value in the postmenopausal range; post-hysterectomy,
             post-bilateral oophorectomy, or post-tubal ligation (documented hysterectomy or
             oophorectomy)

          -  male subjects should agree to use an adequate method of contraception

        Exclusion Criteria:

          -  Patients with uveal and/or mucosal melanoma histology are excluded (Patients with
             melanoma of unknown histology are permitted to enroll)

          -  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 immunosuppression for active autoimmune disease: 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 (>10mg daily prednisone or equivalent) or systemic
             immunosuppressive agents

          -  ≥ CTCAE grade 3 immune-related AE (irAE) experienced with prior immunotherapy (except,
             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, or, development of autoimmune disorders of Grade ≤ 3
             may enroll if the disorder has resolved to Grade ≤ 1)

          -  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 (except ≤ Grade 2
             neuropathy)

          -  autoimmune disorders of Grade 4 while on prior immunotherapy

          -  active (i.e., symptomatic or growing) central nervous system (CNS) and/or
             leptomeningeal metastases (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)

          -  known additional malignancy that is progressing or requires active treatment (except,
             basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ
             cervical cancer that has undergone potentially curative therapy)

          -  invasive cancer diagnosed and treated less than 2 years prior to current presentation
             (other indolent malignancies that are not progressing and/or deemed to require active
             therapy are not exclusionary)

          -  evidence of interstitial lung disease or active, non-infectious pneumonitis

          -  active infection requiring systemic therapy

          -  history or current evidence of any condition, therapy, or laboratory abnormality
             determined to be significant, in the opinion of the treating investigator

          -  known psychiatric or substance abuse disorders that would interfere with study
             compliance

          -  is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial

          -  had a live vaccine within 30 days of initiating protocol therapy

          -  received prior therapy with an IDO inhibitor, anti-PD-1, anti-PD-L1, anti-PD-L2,
             anti-CD137 and/or combination (including nivolumab, pembrolizumab or
             ipilimumab/nivolumab). Prior treatment with ipilimumab or interferon alfa is allowed.

          -  history of allergic or hypersensitivity reaction to components or excipients of
             Dostarlimab (TSR-042) and TSR-022, interferon alfa or ipilimumab

          -  known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  known history of or screening test that is positive for hepatitis B virus (HBV; eg,
             HBsAg reactive or HBV DNA detected) or hepatitis C virus (HCV; HCV antibody positive
             and/or HCV RNA quantitative is detected). 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. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Major Pathologic Response (MPR)
Time Frame:54 weeks
Safety Issue:
Description:Proportion of patients with an RVT (residual volume of viable tumor) of ≤10% remaining in post-therapy specimen using immunotherapy-specific pathologic assessment of neoadjuvant treated melanoma specimens.

Secondary Outcome Measures

Measure:Number of Participants Experiencing Adverse Events Attributed to Treatment
Time Frame:Up to 56 months
Safety Issue:
Description:Number o f participants experiencing adverse events (per CTCAE v5.0) that are possibly, probably or definitely related to study treatment, will be tabulated by category, grade and relatedness.
Measure:Frequency of Delays in Surgery
Time Frame:Up to 56 months
Safety Issue:
Description:Number of delayed of surgeries.
Measure:Frequency of Cancellations of Surgery
Time Frame:Up to 56 months
Safety Issue:
Description:Number of canceled surgeries.
Measure:Relapse-free Survival
Time Frame:Up to 56 months
Safety Issue:
Description:The length of time from initiation of study drug(s) until melanoma relapse (disease progression) as defined by RECIST v1.1, or death. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Measure:Overall Survival (OS)
Time Frame:Up to 56 months
Safety Issue:
Description:The length of time from initiation of study drug(s) that patients remain alive.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Diwakar Davar

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