Clinical Trials /

Neoadjuvant Combination Targeted and Immunotherapy for Patients With High-Risk Stage III Melanoma

NCT03554083

Description:

The purpose of this pilot clinical trial is to study how well drug therapies given prior to and after surgery work in treating participants with high-risk stage III melanoma. Patients will receive either the combination of cobimetinib and atezolizumab or the combination of vemurafenib, cobimetinib, and atezolizumab; followed by surgery; followed by atezolizumab treatment. Vemurafenib may stop the growth of melanoma cells by blocking an enzyme needed for cell growth called BRAF. However, this drug only has potential benefit for patients with a mutation in BRAF, and it will only be given to this subset of patients. Cobimetinib blocks another enzyme important for melanoma cell growth, and it also may provide benefit by making the immune response to melanoma more effective. Atezolizumab may provide benefit by making the immune response to melanoma more effective. Giving combined therapy before surgery and atezolizumab after surgery may work better than other approaches in treating patients with high-risk stage III melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Combination Targeted and Immunotherapy for Patients With High-Risk Stage III Melanoma
  • Official Title: Neoadjuvant Therapy for Patients With High Risk Stage III Melanoma: A Pilot Clinical Trial

Clinical Trial IDs

  • ORG STUDY ID: MC1776
  • SECONDARY ID: NCI-2018-01018
  • SECONDARY ID: MC1776
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03554083

Conditions

  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • 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

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm A (vemurafenib, cobimetinib, atezolizumab)
CobimetinibCotellic, GDC-0973, MEK Inhibitor GDC-0973, XL518Arm A (vemurafenib, cobimetinib, atezolizumab)
VemurafenibBRAF (V600E) kinase inhibitor RO5185426, BRAF(V600E) Kinase Inhibitor RO5185426, PLX-4032, PLX4032, RG 7204, RG7204, RO 5185426, ZelborafArm A (vemurafenib, cobimetinib, atezolizumab)

Purpose

The purpose of this pilot clinical trial is to study how well drug therapies given prior to and after surgery work in treating participants with high-risk stage III melanoma. Patients will receive either the combination of cobimetinib and atezolizumab or the combination of vemurafenib, cobimetinib, and atezolizumab; followed by surgery; followed by atezolizumab treatment. Vemurafenib may stop the growth of melanoma cells by blocking an enzyme needed for cell growth called BRAF. However, this drug only has potential benefit for patients with a mutation in BRAF, and it will only be given to this subset of patients. Cobimetinib blocks another enzyme important for melanoma cell growth, and it also may provide benefit by making the immune response to melanoma more effective. Atezolizumab may provide benefit by making the immune response to melanoma more effective. Giving combined therapy before surgery and atezolizumab after surgery may work better than other approaches in treating patients with high-risk stage III melanoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the percentage of patients with stage III BRAFV600 mutated (BRAFm) melanoma
      that achieves a pathologic complete response after 12 weeks of neoadjuvant
      vemurafenib/cobimetinib/atezolizumab (neoadjuvant phase).

      II. To estimate the percentage of patients with stage III BRAF-wild-type (BRAFwt) melanoma
      that achieves a pathologic complete response after 12 weeks of neoadjuvant
      cobimetinib/atezolizumab (neoadjuvant phase).

      III. To assess recurrence-free survival (RFS) in patients with stage III BRAFm melanoma after
      neoadjuvant vemurafenib/cobimetinib/ atezolizumab, surgery, and adjuvant atezolizumab
      (adjuvant phase).

      IV. To assess RFS in patients with stage III BRAFwt melanoma after neoadjuvant
      cobimetinib/atezolizumab, surgery, and adjuvant atezolizumab (adjuvant phase).

      SECONDARY OBJECTIVES:

      I. To determine the frequency of adverse events among patients with stage III BRAFm melanoma
      receiving neoadjuvant vemurafenib / cobimetinib / atezolizumab followed by surgery followed
      by adjuvant atezolizumab.

      II. To determine the frequency of adverse events among patients with stage III BRAFwt
      melanoma receiving neoadjuvant cobimetinib/atezolizumab followed by surgery followed by
      adjuvant atezolizumab.

      TRANSLATIONAL OBJECTIVES:

      I. To determine the association between pretreatment, on treatment, post-neoadjuvant and
      post-adjuvant treatment soluble PD-L1 (sPD-L1) and RFS in patients with stage III melanoma
      receiving neoadjuvant vemurafenib / cobimetinib / atezolizumab or cobimetinib/atezolizumab,
      followed by surgery and adjuvant atezolizumab.

      II. To determine the association between pretreatment, on treatment, post-neoadjuvant and
      post-adjuvant treatment intracellular bim in tumor-related T cells and RFS in patients with
      stage III melanoma after neoadjuvant vemurafenib/cobimetinib/atezolizumab or
      cobimetinib/atezolizumab, followed by surgery and adjuvant atezolizumab.

      III. Evaluate associations between pre and post-neoadjuvant treatment molecular features of
      melanomas and the tumor immune microenvironment in responders versus non-responders with
      multiplexed immunohistochemistry (mIHC) and ribonucleic acid-sequencing (RNA-Seq) in patients
      with stage III melanoma after neoadjuvant vemurafenib/cobimetinib/atezolizumab or
      cobimetinib/atezolizumab, followed by surgery and adjuvant atezolizumab.

      IV. To determine the association between pretreatment tumor PD-L1 and RFS in patients with
      stage III melanoma receiving neoadjuvant vemurafenib/ cobimetinib/ atezolizumab or
      cobimetinib/atezolizumab, followed by surgery and adjuvant atezolizumab.

      OUTLINE: Participants are assigned to 1 of 2 groups.

      ARM A (BRAF mutant): Participants receive vemurafenib orally (PO) twice daily (BID) on days
      1-28, cobimetinib PO once daily (QD) on days 1-21, and atezolizumab intravenously (IV) over
      30-60 minutes on days 1 and 15 of courses 2 and 3. Treatment repeats every 28 days for up to
      3 courses in the absence of disease progression or unacceptable toxicity.

      ARM B (BRAF wild-type): Participants receive cobimetinib as in Arm A, and atezolizumab IV
      over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 3 courses in
      the absence of disease progression or unacceptable toxicity.

      Within 2-4 weeks after treatment, participants undergo surgery then receive atezolizumab IV
      over 30-60 minutes on day 1. Treatment repeat every 21 days for up to 8 courses in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed every 3 months for up to 3
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (vemurafenib, cobimetinib, atezolizumab)ExperimentalParticipants receive vemurafenib PO BID on days 1-28, cobimetinib PO QD on days 1-21, and atezolizumab IV over 30-60 minutes on days 1 and 15 of courses 2 and 3. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, participants undergo surgery then receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeat every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Cobimetinib
  • Vemurafenib
Arm B (cobimetinib, atezolizumab)ExperimentalParticipants receive cobimetinib as in Arm A, and atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, participants undergo surgery then receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeat every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Cobimetinib

Eligibility Criteria

        Inclusion Criteria:

          -  PRE-REGISTRATION: High-risk stage III melanoma, defined as (any of the following):

               -  Recurrent nodal metastasis, or

               -  Clinically detectable nodal metastasis, or

               -  Metastatic involvement of more than one nodal basin

               -  NOTE: For the purpose of pre-registration, high-risk stage III melanoma is
                  defined based on clinical and imaging assessment (positron emission
                  tomography/computed tomography [PET/CT], CT, or magnetic resonance imaging
                  [MRI]). Histologic confirmation of nodal metastatic disease is not needed at the
                  time of pre-registration, provided there is histologic confirmation of primary
                  melanoma or a prior lymph node metastasis.

          -  PRE-REGISTRATION: Willing to submit archival tissue from a lymph node biopsy or
             undergo a needle biopsy for BRAF testing and for research purposes.

          -  PRE-REGISTRATION: Willing to forego anticancer treatments or investigational agents
             during pre-registration period.

          -  PRE-REGISTRATION: The following laboratory values obtained =< 28 days prior to
             pre-registration:

               -  Only for patients receiving therapeutic anticoagulation: stable anticoagulant
                  regimen and stable international normalized ratio (INR).

          -  REGISTRATION: Histologic confirmation of stage III melanoma, as defined by the
             American Joint Committee on Cancer, 8th revised edition.

          -  REGISTRATION: Documentation of BRAFV600 mutation status in melanoma tumor tissue
             (archival or newly obtained) through use of a Clinical Laboratory Improvement
             Amendments (CLIA)-approved clinical mutation test.

          -  REGISTRATION: Surgically resectable disease, as determined by a melanoma surgical
             oncologist.

          -  REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  REGISTRATION: Life expectancy >= 26 weeks.

          -  REGISTRATION: Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior
             to registration.

          -  REGISTRATION: Platelet count >= 100,000/mm^3 obtained =< 14 days prior to
             registration.

          -  REGISTRATION: Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to registration.

          -  REGISTRATION: Direct bilirubin =< institutional upper limit of normal (ULN) obtained
             =< 14 days prior to registration.

          -  REGISTRATION: Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2 x ULN
             obtained =< 14 days prior to registration.

          -  REGISTRATION: Alkaline phosphatase < 2.5 x ULN obtained =< 14 days prior to
             registration.

          -  Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min on the basis of
             measured CrCl from a 24-hour urine collection or Cockcroft-Gault glomerular filtration
             rate estimation obtained =< 14 days prior to registration.

          -  REGISTRATION: Left ventricular ejection fraction (LVEF) >= 50% or institutional lower
             limit of normal (LLN) =< 6 months prior to registration.

          -  REGISTRATION: Average corrected QT interval (QTc) =< 450 ms on triplicate 12 lead
             electrocardiography (ECG) =< 28 days prior to registration.

          -  REGISTRATION: Negative pregnancy test done =< 7 days prior to registration, for
             persons of childbearing potential only.

          -  REGISTRATION: For persons of childbearing potential: agreement to remain abstinent
             (refrain from heterosexual intercourse) or use a contraceptive method with a failure
             rate of < 1% per year during the treatment period and for 6 months after the last dose
             of study treatment.

          -  REGISTRATION: For persons able to father a child: agreement to remain abstinent
             (refrain from heterosexual intercourse with a person of childbearing potential) or use
             contraceptive measures, and agreement to refrain from donating sperm.

          -  REGISTRATION: Provide written informed consent.

          -  REGISTRATION: Willing to return to enrolling institution for follow-up (during the
             active monitoring phase of the study).

          -  REGISTRATION: Willing to provide tissue, blood, and stool samples for correlative
             research purposes.

        Exclusion Criteria:

          -  PRE-REGISTRATION: Prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy,
             hormonal therapy, targeted therapy, immunotherapy including anti-PD-1, anti-PDL1
             agents, or other biologic therapies), with the following exceptions: adjuvant
             treatment with interferon, IL-2, granulocyte-macrophage colony-stimulating factor
             (GM-CSF) or vaccine therapies are allowed, if discontinued >= 28 days prior to
             pre-registration.

          -  PRE-REGISTRATION: Receiving any other investigational agent which would be considered
             as a treatment for the primary neoplasm.

          -  PRE-REGISTRATION: For patients with concurrent diagnosis of primary melanoma with
             nodal involvement, major surgical procedure other than lymph node biopsy or wide local
             excision of primary melanoma =< 4 weeks prior to pre-registration, or anticipation of
             need for a major surgical procedure for reasons other than melanoma during the course
             of the study.

          -  PRE-REGISTRATION: For patients with nodal recurrence, surgical procedure or
             anti-cancer therapy for this recurrence (other than lymph node biopsy) or anticipation
             of need for a major surgical procedure for reasons other than melanoma during the
             course of the study.

          -  PRE-REGISTRATION: Prior radiotherapy for melanoma.

          -  PRE-REGISTRATION: History non-nodal melanoma metastasis or central nervous system
             (CNS) lesion(s) proven or clinically suspected to be metastasis.

          -  PRE-REGISTRATION: Active malignancy (other than melanoma) or malignancy =< 3 years
             prior to pre-registration.

               -  NOTE: with the exception of resected basal cell carcinoma (BCC), resected
                  cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the
                  cervix, resected carcinoma in situ of the breast, in situ prostate cancer,
                  non-muscle-invasive bladder cancer, or other curatively treated malignancies from
                  which the patient has been disease-free for at least 3 years prior to
                  pre-registration.

          -  PRE-REGISTRATION: Prior allogeneic stem cell or solid organ transplantation.

          -  PRE-REGISTRATION: History of idiopathic pulmonary fibrosis, organizing pneumonia
             (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,
             or evidence of active pneumonitis on screening chest CT scan.

          -  PRE-REGISTRATION: History of autoimmune disease requiring systemic immunosuppressive
             or immune-modulatory therapy =< 5 years prior to pre-registration.

          -  PRE-REGISTRATION: Active psoriasis requiring therapy (systemic or topical).

          -  PRE-REGISTRATION: Known clinically significant liver disease, including alcoholism,
             cirrhosis, fatty liver, and other inherited liver disease as well as active viral
             disease.

          -  PRE-REGISTRATION: History of or evidence of retinal pathology on ophthalmologic
             examination including but not limited to:

               -  Neurosensory retinal detachment

               -  Central serous chorioretinopathy

               -  Retinal vein occlusion (RVO)

               -  Neovascular macular degeneration

          -  PRE-REGISTRATION: Immunocompromised patients and patients known to be human
             immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.

               -  NOTE: Patients known to be HIV positive, but without clinical evidence of an
                  immunocompromised state, are eligible for this trial.

          -  PRE-REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:

               -  Ongoing or active infection

               -  Clinically significant cardiac dysfunction including:

                    -  Symptomatic congestive heart failure defined as New York Heart Association
                       class II or higher

                    -  Unstable angina pectoris or new-onset angina =< 3 months prior to
                       pre-registration

                    -  Unstable cardiac arrhythmia

                    -  Myocardial infarction =< 3 months prior to pre-registration

                    -  Congenital long QT syndrome

               -  Clinically significant stroke, reversible ischemic neurological defect, or
                  transient ischemic attack =< 6 months prior to pre-registration

               -  Any grade 3 hemorrhage or bleeding event =< 4 weeks prior to pre-registration

               -  Uncontrolled diabetes or symptomatic hyperglycemia

               -  Psychiatric illness/social situations that, in the judgement of the investigator,
                  would a) limit compliance with study requirements, b) make the patient
                  inappropriate for entry into this study, or c) interfere significantly with the
                  proper assessment of safety and toxicity of the prescribed regimens.

          -  PRE-REGISTRATION: Known hypersensitivity to biopharmaceutical agents produced in
             Chinese hamster ovary cells (example [ex]: recombinant follicle-stimulating hormone
             [FSH]).

          -  PRE-REGISTRATION: Known hypersensitivity to any components of the atezolizumab,
             cobimetinib, or vemurafenib formulations.

          -  PRE-REGISTRATION: History of severe allergic, anaphylactic or other hypersensitivity
             reactions to chimeric or humanized antibodies or fusion proteins.

          -  REGISTRATION: Received anticancer treatments or investigational agents during
             pre-registration period.

          -  REGISTRATION: Clinically suspected non-nodal metastatic melanoma.

          -  REGISTRATION: For BRAF-mutant patients only: anticipated use of any concomitant
             medication =< 7 days prior to registration that is known to cause QT prolongation
             (which may lead to torsade de pointes).

          -  REGISTRATION: History of malabsorption or other clinically significant metabolic
             dysfunction that may interfere with absorption of oral study treatment or inability or
             unwillingness to swallow oral medication.

          -  REGISTRATION: Signs or symptoms of infection or has received antibiotics ≤14 days
             prior to registration.

               -  NOTE: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary
                  tract infection or chronic obstructive pulmonary disease exacerbation) are
                  eligible for the study.

          -  REGISTRATION: Any of the following because this study involves investigational agents
             whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
             are unknown:

               -  Pregnant persons

               -  Nursing persons

               -  Persons of childbearing potential who are unwilling to employ adequate
                  contraception

          -  REGISTRATION: Treatment with a live, attenuated vaccine =< 4 weeks prior to
             registration, or anticipation of need for such a vaccine during the course of the
             study.

          -  REGISTRATION: Treatment with systemic immunosuppressive medication (including, but not
             limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-tumor necrosis factor (TNF)-alpha agents) =< 2 weeks prior to registration, or
             anticipation of need for systemic immunosuppressive medication during the course of
             the study.

               -  NOTE: Patients who have received acute, low-dose systemic steroids (=< 10 mg/day
                  oral prednisone or equivalent) prior to registration or a one-time pulse dose of
                  systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a
                  contrast allergy) are eligible for the study.

               -  NOTE: The use of inhaled corticosteroids for chronic obstructive pulmonary
                  disease or asthma, mineralocorticoids (e.g., fludrocortisone), or low-dose
                  corticosteroids for patients with orthostatic hypotension or adrenocortical
                  insufficiency is allowed.

          -  REGISTRATION: Requirement for concomitant therapy or food that is prohibited during
             the study, or inability to abstain from alcohol during neoadjuvant phase.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response rate (pCR) in participants with stage III BRAFm (mutant) melanoma (neoadjuvant phase)
Time Frame:After 12 weeks of therapy
Safety Issue:
Description:Pathologic complete response rate defined as the percentage of participants with no residual disease found in the surgical specimen among the patients who began neo-adjuvant protocol treatment. An interval estimate will be obtained using the formula for a 90% binomial confidence interval for one sample proportion.

Secondary Outcome Measures

Measure:Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) (neoadjuvant phase)
Time Frame:After 12 weeks of therapy
Safety Issue:
Description:For each cohort, the frequency and severity of toxicities will be documented using the CTCAE criteria and tabulated for the neo-adjuvant phase and post-operative visit separately.
Measure:Change in the uptake on Positron emission tomography (PET)/computed tomography (CT) results
Time Frame:5.5 years after study enrollment begins
Safety Issue:
Description:For each cohort, the percent change in the uptake on PET/CT scan taken at the completion of neo-adjuvant treatment from that on PET/CT scan taken prior to the start of neo-adjuvant treatment will be determined. Also, the appearance of new sites of uptake in the post neo-adjuvant treatment scan and lack of uptake in the areas where uptake was seen in the pre-treatment scan will be noted.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

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