Clinical Trials /

Pembrolizumab in Treating Patients With Stage III-IV High-Risk Melanoma Before and After Surgery

NCT03698019

Description:

This phase II trial studies how pembrolizumab works before and after surgery in treating patients with stage III-IV high-risk melanoma. 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. Giving pembrolizumab before and after surgery may work better in treating melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Treating Patients With Stage III-IV High-Risk Melanoma Before and After Surgery
  • Official Title: A Phase II Randomized Study of Adjuvant Versus NeoAdjuvant MK-3475 (Pembrolizumab) for Clinically Detectable Stage III-IV High-Risk Melanoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-02107
  • SECONDARY ID: NCI-2018-02107
  • SECONDARY ID: S1801
  • SECONDARY ID: S1801
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03698019

Conditions

  • Acral Lentiginous Melanoma
  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Mucosal Melanoma
  • Pathologic Stage III Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIA Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIID Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm I (adjuvant pembrolizumab)

Purpose

This phase II trial studies how pembrolizumab works before and after surgery in treating patients with stage III-IV high-risk melanoma. 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. Giving pembrolizumab before and after surgery may work better in treating melanoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare event-free survival (EFS) in patients with high-risk resectable melanoma
      randomized to neoadjuvant MK-3475 (pembrolizumab) with patients randomized to adjuvant
      MK-3475 (pembrolizumab).

      SECONDARY OBJECTIVES:

      I. To assess the frequency and severity of toxicities on each of the arms. II. To compare
      between arms overall survival (OS), disease control at 24 weeks, locoregional control in the
      surgical site(s), and total number of MK-3475 (pembrolizumab) doses received.

      III. On the neoadjuvant arm, to estimate the pathologic response rate, the Response
      Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate (confirmed complete response
      [CR] and partial response [PR]), and the immune-related (i)RECIST response rate (confirmed CR
      and PR), before surgical resection; to compare definitions of pathologic partial response;
      and to evaluate the association between pathologic response and EFS and OS.

      IV. To describe the proportion of patients on each arm who received the surgery planned at
      randomization.

      ADDITIONAL OBJECTIVES:

      I. To bank tumor tissue and whole blood in anticipation of future correlative studies in this
      patient population.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Within 84 days after surgical resection, patients receive pembrolizumab intravenously
      (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 courses in the absence
      of disease progression or unacceptable toxicity.

      ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3
      courses, then undergo surgical resection within 3 weeks. Within 84 days, patients receive
      pembrolizumab IV over 30 minutes every 3 weeks for 15 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 3 and 12 weeks, then every
      3, 6, or 12 months for up to 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (adjuvant pembrolizumab)ExperimentalWithin 84 days after surgical resection, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 courses in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
Arm II (adjuvant and neoadjuvant pembrolizumab)Active ComparatorPatients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 courses, then undergo surgery within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 courses in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  STEP 1 REGISTRATION (RANDOMIZATION)

          -  Patients must have resectable melanoma in order to be eligible for this study.
             Patients must have clinically detectable Stage III (clinically detectable N1b, N1c,
             N2b, N2c, N3b and N3c) or Stage IV resectable melanoma. Patients with melanoma of
             mucosal or acral origin are eligible. Patients with melanoma of uveal origin are not
             eligible. Patients with a history of brain metastases are not eligible. Clinically
             detectable is defined as disease that is apparent and measurable via physical
             examination or radiographic imaging.

          -  Patients are eligible for this trial either at initial presentation of their melanoma
             or at the time of the first detected nodal, satellite/in-transit, distant metastases,
             or recurrent disease in prior lymphadenectomy basin or distant site. Nodal,
             satellite/in-transit metastasis, distant metastases or disease in a prior complete
             lymphadenectomy basin must have been confirmed histologically by hematoxylin (H) &
             eosin (E) stained slides.

          -  Patients with multiple regional nodal basin involvement are eligible. Gross or
             microscopic extracapsular nodal extension is permitted.

          -  Patients must not have received previous neoadjuvant treatment for their melanoma.
             Patients may have received prior non-immunotherapy adjuvant therapy. Patients must not
             have had prior immunotherapy including, but not limited to ipilimumab, interferon
             alfa-2b, high dose, pegylated interferon (PEG-IFN), anti-PD-1, anti-PD-L1
             intra-tumoral, or vaccine therapies. Patients must not be planning to receive any of
             the prohibited therapies during treatment phases on the study.

          -  Patients must not be planning to receive concomitant other biologic therapy, hormonal
             therapy, other chemotherapy, surgery, while on protocol therapy.

          -  Patients may have received prior radiation therapy, including after prior surgical
             resection. All adverse events associated with prior surgery and radiation therapy must
             have resolved to =< Grade 1 prior to randomization.

          -  All patients must have disease status documented by a complete physical examination
             and imaging studies within 42 days prior to randomization. Imaging studies must
             include a total body positron emission tomography (PET)-computerized tomography (CT)
             scan that is of diagnostic quality with iodine contrast-enhanced images (with or
             without brain) or a CT of the chest, abdomen and pelvis with intravenous contrast. For
             patients with melanoma arising from the head and neck, dedicated neck imaging (CT with
             intravenous contrast or iodine contrast-enhanced PET-CT through the region) is
             required. If the patient has unknown primary with disease in the axilla, neck imaging
             is required to assure region is clear of cancer. CT imaging should be done with
             intravenous contrast if there are no contraindications for it. Any other
             clinically-indicated imaging studies if performed (e.g. bone scan) must show no
             evidence of disease.

          -  All patients must have a CT or magnetic resonance imaging (MRI) of the brain within 42
             days prior to randomization. The brain CT or MRI should be performed with intravenous
             contrast (unless contraindicated).

          -  Absolute neutrophil count (ANC) >= 1,500/microliter (mcL) (within 42 days prior to
             randomization).

          -  Platelets >= 100,000/mcL (within 42 days prior to randomization).

          -  Hemoglobin >= 10 g/dL (within 42 days prior to randomization).

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except patients
             with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 42 days
             prior to randomization).

          -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
             serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2 x
             IULN (within 42 days prior to randomization).

          -  Alkaline phosphatase =< 2 x IULN (within 42 days prior to randomization).

          -  Patients must have lactate dehydrogenase (LDH) performed within 42 days prior to
             randomization.

          -  Patients must have adequate creatinine clearance as evidenced by creatinine clearance
             (CrCl) > 30 mL/min within 42 days prior to randomization.

          -  Patients must have Zubrod Performance Status =< 2.

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

          -  Patients must not have an active infection requiring systemic therapy.

          -  Patients must not have active autoimmune disease that has required systemic treatment
             in past 2 years (i.e., with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment.

          -  Patients must not have received live vaccines within 42 days prior to randomization.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin
             (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are
             generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.

          -  Patients known to be human immunodeficiency virus (HIV) positive are eligible if they
             meet the following criteria within 30 days prior to randomization: stable and adequate
             CD4 counts (>= 350 mm^3), and serum HIV viral load of < 25,000 IU/ml. Patients may be
             on or off anti-viral therapy so long as they meet the CD4 count criteria.

          -  Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV)
             infection prior to randomization. Note: No testing for hepatitis B and hepatitis C is
             required unless mandated by local health authority.

          -  Prior malignancy is allowed providing it does not require concurrent therapy.

          -  Women of childbearing potential must have a negative urine or serum pregnancy test
             within 28 days prior to randomization. Women/men of reproductive potential must have
             agreed to use an effective contraceptive method for the course of the study through
             120 days after the last dose of study medication. Should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             should inform her treating physician immediately. A woman is considered to be of
             "reproductive potential" if she has had menses at any time in the preceding 12
             consecutive months. In addition to routine contraceptive methods, "effective
             contraception" also includes heterosexual celibacy and surgery intended to prevent
             pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
             bilateral oophorectomy, or bilateral tubal ligation. However, if at any point a
             previously celibate patient chooses to become heterosexually active during the time
             period for use of contraceptive measures outlined in the protocol, he/she is
             responsible for beginning contraceptive measures. Patients must not be pregnant or
             nursing due to unknown teratogenic side effects.

          -  Patients must be deemed medically fit to undergo surgery by the treating
             medical/surgical team.

          -  Patients must be willing to submit the following surgical specimens: either all tissue
             blocks from the surgical specimen or two slides per block ([1] H&E slide and [1]
             unstained slide OR [2] unstained slides if H&E stained slides cannot be provided).

          -  Patients must be offered the opportunity to participate in specimen banking.

          -  Patients must be informed of the investigational nature of this study and must sign
             and give written informed consent for this protocol in accordance with institutional
             and federal guidelines.

          -  As a part of the Oncology Patient Enrollment Network (OPEN) randomization process the
             treating institution's identity is provided in order to ensure that the current
             (within 365 days) date of institutional review board approval for this study has been
             entered in the system.

          -  STEP 2 REGISTRATION (SURGERY)

          -  Patients randomized to Arm 2 (Neoadjuvant arm) must be willing to submit tissue to
             determine pathologic response regardless of number of pre-operative doses of MK-3475
             (pembrolizumab) received. Determination of pathologic response cannot be done on less
             than the full surgical specimen.

          -  Patients must have disease assessments by PET-CT with iodinated CT contrast (i.e.
             diagnostic quality CT) or CT chest/abdomen/pelvis with IV contrast, and neck CT with
             IV contrast if primary head and neck melanoma, performed within 42 days (+/- 1 week)
             before surgery. MRI combined with non-contrast CT is an acceptable alternative for
             patients with CT contrast allergy, but imaging must encompass total body.

          -  STEP 3 REGISTRATION (ADJUVANT THERAPY)

          -  Patients must have undergone surgery prior to Step 3 registration. The Step 2 surgery
             must have completely resected their melanoma.

               -  Patients with gross positive residual disease at the time of surgery do not
                  qualify as having disease-free status, and, therefore, such patients are not
                  eligible to register for adjuvant therapy.

               -  Patients with microscopic residual disease (i.e., positive margins) can be
                  treated with re-excision or radiation, per site discretion, to render the patient
                  disease-free prior to registration of adjuvant therapy.

               -  Disease-free status must be documented by a complete physical examination and
                  radiographic imaging studies within 60 days prior to Step 3 registration. Imaging
                  studies must include a total body PET-CT that is of diagnostic quality (i.e.,
                  iodinated contrast), or a CT of the chest, abdomen, and pelvis.

               -  For patients with melanoma arising from the head and neck, dedicated neck imaging
                  (CT with IV contrast with PET-CT through the region) is required.

               -  If the patient has had unknown primary with disease in the axilla, neck imaging
                  is required to assure the region is clear of cancer.

               -  CT imaging should be done with intravenous contrast if there are no
                  contraindications for it.

               -  Any other clinically-indicated imaging studies if performed (e.g., bone scan)
                  must show no evidence of disease.

          -  Patients must be registered to Step 3 no more than 84 days after date of surgery.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS) in patients with high-risk resectable melanoma randomized to neoadjuvant pembrolizumab with patients randomized to adjuvant pembrolizumab
Time Frame:Date of randomization to date of first progression or death assessed up to 10 years
Safety Issue:
Description:We will use exponential-mixture cure models to describe EFS patterns in the arms.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Up to 10 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and compared between arms using log-rank tests and Cox regression models.
Measure:Disease control
Time Frame:At 24 weeks
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and compared between arms using log-rank tests and Cox regression models.
Measure:Local/regional control in the surgical site(s)
Time Frame:Up to 10 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method and compared between arms using log-rank tests and Cox regression models.
Measure:Total number of pembrolizumab doses
Time Frame:Up to 10 years
Safety Issue:
Description:Will use Fisher's exact test to compare the number of pembrolizumab doses received by patients on each treatment arm.
Measure:Pathologic response rate
Time Frame:Up to 10 years
Safety Issue:
Description:Will be tabulated for the neoadjuvant arm and exact 95% confidence intervals will be constructed.
Measure:Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate
Time Frame:Up to 10 years
Safety Issue:
Description:Will be tabulated for the neoadjuvant arm and exact 95% confidence intervals will be constructed.
Measure:Immune-related (i)RECIST response rate
Time Frame:Up to 10 years
Safety Issue:
Description:Will be tabulated for the neoadjuvant arm and exact 95% confidence intervals will be constructed.

Details

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

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