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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03554083
Recruitment Status : Recruiting
First Posted : June 12, 2018
Last Update Posted : November 20, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Genentech, Inc.
Stand Up To Cancer
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
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 Drug: Atezolizumab Drug: Cobimetinib Drug: Vemurafenib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant Therapy for Patients With High Risk Stage III Melanoma: A Pilot Clinical Trial
Actual Study Start Date : June 22, 2018
Estimated Primary Completion Date : June 29, 2023
Estimated Study Completion Date : June 29, 2023


Arm Intervention/treatment
Experimental: Arm A (vemurafenib, cobimetinib, atezolizumab)

Participants 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.

Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Drug: Cobimetinib
Given PO
Other Names:
  • Cotellic
  • GDC-0973
  • MEK Inhibitor GDC-0973
  • XL518

Drug: Vemurafenib
Given PO
Other Names:
  • BRAF (V600E) kinase inhibitor RO5185426
  • BRAF(V600E) Kinase Inhibitor RO5185426
  • PLX-4032
  • PLX4032
  • RG 7204
  • RG7204
  • RO 5185426
  • Zelboraf

Experimental: Arm B (cobimetinib, atezolizumab)
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.
Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Drug: Cobimetinib
Given PO
Other Names:
  • Cotellic
  • GDC-0973
  • MEK Inhibitor GDC-0973
  • XL518




Primary Outcome Measures :
  1. Pathologic complete response rate (pCR) in participants with stage III BRAFm (mutant) melanoma (neoadjuvant phase) [ Time Frame: After 12 weeks of therapy ]
    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.

  2. Pathologic complete response rate in participants with stage III BRAFwt (wild type) melanoma (neoadjuvant phase) [ Time Frame: After 12 weeks of therapy ]
    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.

  3. Median recurrence-free (RFS) rate (adjuvant phase) [ Time Frame: From surgery assessed up to 3 years ]
    Recurrence-free survival is defined as the time from surgery to radiographic or histologic evidence of local, regional, or distant recurrence of melanoma or death due to any cause. For each regimen, the distribution of recurrence-free survival times [denoted as RFS(t)] will be estimated using the Kaplan-Meier method. A 90% confidence interval for V(t) = log [-log (RFS(t)] will be constructed and then the inverse transformation exp[-exp v(t)] will be used to obtain a confidence for RFS(t).


Secondary Outcome Measures :
  1. Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) (neoadjuvant phase) [ Time Frame: After 12 weeks of therapy ]
    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.

  2. Change in the uptake on Positron emission tomography (PET)/computed tomography (CT) results [ Time Frame: 5.5 years after study enrollment begins ]
    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.


Other Outcome Measures:
  1. Pretreatment soluble (s)PD-L1, pretreatment tumor PD-L1, and pretreatment intracellular Bim in tumor-related T cells [ Time Frame: Up to 3 years ]
    Stratified Cox modeling will be conducted with participant cohort as the strata to obtain a point and interval estimate of the hazard of recurrence among those with biomarker levels thought to be delirious relative to the hazard of recurrence among those with biomarker levels thought not to be delirious.

  2. Molecular features of melanomas and the tumor immune microenvironment evaluated with multiplexed immunohistochemistry (mIHC) and ribonucleic acid sequencing (RNASeq) [ Time Frame: Up to 3 years ]
    Graphs will be constructed to visually compare and contrast the levels of these biomarkers between those who achieve a pCR and those who did not. Binomial confidence intervals for the difference in two independent proportions or t confidence intervals for the difference in two independent means will be used to gain preliminary insights into the difference in these biomarkers among those who achieve a pCR and those who did not.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03554083


Locations
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United States, Florida
Mayo Clinic Florida Recruiting
Jacksonville, Florida, United States, 32224
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Roxana S. Dronca, MD         
United States, Minnesota
University of Minnesota/Masonic Cancer Center Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Clinical Trials Office    612-624-2620      
Principal Investigator: Evidio Domingo-Musibay, M.D.         
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Matthew S. Block, M.D., Ph.D.         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Genentech, Inc.
Stand Up To Cancer
Investigators
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Principal Investigator: Matthew Block Mayo Clinic
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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03554083    
Other Study ID Numbers: MC1776
NCI-2018-01018 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1776 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: June 12, 2018    Key Record Dates
Last Update Posted: November 20, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Melanoma
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Atezolizumab
Vemurafenib
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action