Clinical Trials /

A Study Evaluating Whether Pembrolizumab Alone or in Combination With CMP-001 Improves Efficacy in Patients With Operable Melanoma

NCT04708418

Description:

This phase II trial studies the effect of pembrolizumab alone or in combination with CMP-001 in treating patients with melanoma that can be treated by surgery (operable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with CMP-001 may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. The addition of CMP-001 to pembrolizumab could improve the ability of the immune system to shrink tumors and to prevent them from returning.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating Whether Pembrolizumab Alone or in Combination With CMP-001 Improves Efficacy in Patients With Operable Melanoma
  • Official Title: Phase II Randomized Study of Neoadjuvant Pembrolizumab Alone or in Combination With CMP-001 in Patients With Operable Melanoma: Efficacy and Biomarker Study

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-14174
  • SECONDARY ID: NCI-2020-14174
  • SECONDARY ID: EA6194
  • SECONDARY ID: EA6194
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04708418

Conditions

  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Melanoma of Unknown Primary
  • Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIID Cutaneous Melanoma AJCC v8
  • Recurrent Cutaneous Melanoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm A (pembrolizumab)
VLP-encapsulated TLR9 Agonist CMP-001ARB-1598, CMP-001, CYT 003, CYT-003Arm B (CMP-001, pembrolizumab)

Purpose

This phase II trial studies the effect of pembrolizumab alone or in combination with CMP-001 in treating patients with melanoma that can be treated by surgery (operable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with CMP-001 may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. The addition of CMP-001 to pembrolizumab could improve the ability of the immune system to shrink tumors and to prevent them from returning.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the rate of pathologic complete response (pCR) rate in each arm.

      SECONDARY OBJECTIVES:

      I. To evaluate the rate of pathologic near-complete/major response (pMR) of the neoadjuvant
      therapy in each arm.

      II. To evaluate the pathologic response rate of un-injected lesions on the combination arm.

      III. To evaluate relapse-free survival (RFS) in each arm. IV. To evaluate overall survival
      (OS) in each arm. V. To evaluate the preoperative radiographic response rate in each arm. VI.
      To evaluate safety and toxicity of neoadjuvant therapy in each arm.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A:

      NEOADJUVANT PHASE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day
      1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression
      or unacceptable toxicity.

      SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.

      ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30
      minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in
      the absence of disease progression or unacceptable toxicity.

      ARM B:

      NEOADJUVANT PHASE: Patients receive VLP-encapsulated TLR9 agonist CMP-001 (CMP-001)
      subcutaneously (SC) on day 1 of cycle 1 and then intratumorally on days 8 and 15 of cycle 1,
      days 1, 8, and 15 of cycle 2, and day 1 of cycle 3. Patients also receive pembrolizumab IV
      over 30 minutes on day 8 of each cycle. Treatment repeats every 21 days for up to 3 cycles in
      the absence of disease progression or unacceptable toxicity.

      SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.

      ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30
      minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 3
      months if < 2 years from study entry, every 6 months if 2-5 years from study entry, and every
      12 months if > 5 years from study entry for up to 10 years (15 years total follow up).
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (pembrolizumab)ExperimentalNEOADJUVANT PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase. ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
Arm B (CMP-001, pembrolizumab)ExperimentalNEOADJUVANT PHASE: Patients receive CMP-001 SC on day 1 of cycle 1 and then intratumorally on days 8 and 15 of cycle 1, days 1, 8, and 15 of cycle 2, and day 1 of cycle 3. Patients also receive pembrolizumab IV over 30 minutes on day 8 of each cycle. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase. ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • VLP-encapsulated TLR9 Agonist CMP-001

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must be >= 18 years of age

          -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
             or 1

          -  Patient must have a histologic diagnosis of melanoma belonging to the following
             American Joint Committee on Cancer (AJCC) 8th edition TNM stages:

               -  T0, Tx or T1-4; and

               -  N2b, N2c, N3b or N3c

          -  Patients may have a presentation with primary melanoma with concurrent regional nodal
             and/or in-transit metastasis; or patients may have a history of primary melanoma or
             unknown primary melanoma presenting with clinically detected regional nodal and/or
             in-transit recurrence; and may belong to any of the following groups:

               -  Primary cutaneous melanoma with clinically apparent regional lymph node
                  metastases and/or in-transit metastases

               -  Clinically detected recurrent melanoma at the proximal regional lymph node(s)
                  basin

               -  Primary cutaneous melanoma with concurrent nodal disease involving a single
                  regional nodal group

               -  Clinically detected nodal melanoma (if single site) arising from an unknown
                  primary

               -  In-transit cutaneous metastases with or without regional lymph node involvement
                  permitted if considered potentially surgically resectable at baseline

                    -  NOTE: Patients with mucosal and/or uveal melanoma are not eligible for the
                       study

          -  Patient must be candidate for definitive surgery and have met with the treating
             surgical oncologist prior to randomization

          -  Patient must have the presence of injectable and measurable disease based on Response
             Evaluation Criteria in Solid Tumors (RECIST) 1.1, documented by scans obtained within
             4 weeks prior to randomization

               -  NOTE: Injectable disease is defined as an accessible lesion in the skin,
                  subcutaneous tissue or lymph nodes (LN) close to the skin and palpable by
                  physical examination or approachable with ultrasound guidance

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL (obtained within 4 weeks prior to
             randomization)

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (obtained within 4 weeks prior to randomization)

          -  Platelets >= 100,000 / mcL (obtained within 4 weeks prior to randomization)

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or measured or calculated
             creatinine clearance > 60 mL/min (glomerular filtration rate [GFR] can also be used in
             place of creatinine or creatinine clearance [CrCl] for patients with creatinine levels
             > 1.5 x institutional ULN) (obtained within 4 weeks prior to randomization)

          -  Serum total bilirubin =< 1.5 x ULN; for total bilirubin levels > 1.5 x ULN, but =< 3 x
             ULN, the direct bilirubin must be =< the ULN (obtained within 4 weeks prior to
             randomization)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN (obtained within 4 weeks prior to randomization)

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants (obtained
             within 4 weeks prior to randomization)

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants (obtained within 4 weeks prior to randomization)

          -  Patient must have the ability to understand and the willingness to sign a written
             informed consent document. Patients with impaired decision-making capacity (IDMC) who
             have a legally authorized representative (LAR) or caregiver and/or family member
             available will also be considered eligible

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

        Exclusion Criteria:

          -  Patient must not have received any live vaccine within 30 days prior to randomization.
             Live vaccines include, but are not limited to, the following: measles, mumps, rubella,
             chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral)
             vaccine

          -  Women must not be pregnant or breast-feeding due to the potential harm to an unborn
             fetus and possible risk for adverse events in nursing infants with the treatment
             regimens being used. All females of childbearing potential must have a blood test or
             urine study within 14 days prior to randomization to rule out pregnancy. A urine or
             serum pregnancy test must be repeated within 72 hours prior to receiving the first
             dose of pembrolizumab if the test done for eligibility/randomization is done outside
             of this 72 hour window. If the urine test is positive or cannot be confirmed as
             negative, a serum pregnancy test will be required. A female of childbearing potential
             is defined as any woman, regardless of sexual orientation or whether they have
             undergone tubal ligation, who meets the following criteria: 1) has achieved menarche
             at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3)
             has not been naturally postmenopausal (amenorrhea following cancer therapy does not
             rule out childbearing potential) for at least 24 consecutive months (i.e., has had
             menses at any time in the preceding 24 consecutive months)

          -  Women of childbearing potential and sexually active males must not expect to conceive
             or father children by using accepted and effective method(s) of contraception or
             abstaining from sexual intercourse from time of randomization, while on study
             treatment, and continue for 26 weeks after the last dose of protocol treatment

          -  Patient must not have received prior systemic therapy for melanoma including systemic
             therapy with an anti-PD-1, anti-PD-L1, anti-CTLA-4, BRAF/MEK inhibitor combination
             and/or TLR-9 agonist

          -  Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid
             therapy or any other form of immunosuppressive therapy within 7 days prior to
             randomization, except as noted here

               -  Patients who are currently receiving steroids at a dose of prednisone =< 5 mg
                  daily (or equivalent) are permitted to enroll

               -  Patients who require topical, ophthalmologic and inhalational steroids are
                  permitted to enroll

               -  Patients with hypothyroidism who are stable on hormone replacement are permitted
                  to enroll

               -  Patients who require active immunosuppression with corticosteroids at a dose of
                  prednisone > 5 mg daily (or equivalent) for any reason are ineligible

               -  Patients with adrenal insufficiency are ineligible

               -  Patients who have developed autoimmune disorders of grade 4 while on prior
                  immunotherapy are not permitted to enroll on this study. Patients who developed
                  autoimmune disorders of grade =< 3 may enroll if the disorder has resolved to
                  grade =< 1 and the patient has been off systemic corticosteroids at doses > 5 mg
                  for at least 2 weeks prior to randomization

          -  Patients with a history of brain metastases are not eligible for this study as they do
             not meet the eligibility staging criteria

          -  Patient must not have an allogeneic tissue/solid organ transplant

          -  Patient must not have a history of (non-infectious) pneumonitis that required steroids
             or current pneumonitis

          -  Patient must not have severe hypersensitivity (>= grade 3) to pembrolizumab and/or any
             of its excipients

          -  Patient must not have an active infection requiring systemic therapy

          -  Patient must not have a known psychiatric or substance abuse disorder that would
             interfere with the participant's ability to cooperate with the requirements of the
             study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response rate
Time Frame:Up to 15 years
Safety Issue:
Description:Will be estimated by the percentage of patients who achieve complete response, partial response or stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) and Immune-Modified (i)RECIST criteria, with exact 90% confidence intervals.

Secondary Outcome Measures

Measure:Radiographic response rate
Time Frame:Up to 15 years
Safety Issue:
Description:Will be assessed using RECIST.
Measure:Relapse-free survival
Time Frame:From randomization to relapse or death (whichever occurs first), assessed up to 15 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:From randomization to death from any cause, assessed up to 15 years
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 30 days after the last study drug administration
Safety Issue:
Description:Patients will be monitored for adverse events using the National Cancer Institute's Common Terminology Criteria for Adverse Events.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

June 8, 2021