Neoadjuvant Therapy for Patients With High Risk Stage III Melanoma: A Pilot Clinical Trial

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



Sponsors


Source

Mayo Clinic

Oversight Info

Has Dmc

Yes

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No

Is Us Export

No


Brief Summary

This early phase I pilot trial studies how well vemurafenib, cobimetinib, and atezolizumab
work in treating participants with high-risk stage III melanoma. Vemurafenib and cobimetinib
may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to
grow and spread. Giving vemurafenib, cobimetinib, and atezolizumab may work better in
treating 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.

Overall Status

Recruiting

Start Date

2018-06-22

Completion Date

2023-06-29

Primary Completion Date

2023-06-29

Phase

Early Phase 1

Study Type

Interventional

Primary Outcome

Measure

Time Frame

Pathologic complete response rate (pCR) in participants with stage III BRAFm (mutant) melanoma (neoadjuvant phase)
After 12 weeks of therapy
Pathologic complete response rate in participants with stage III BRAFwt (wild type) melanoma (neoadjuvant phase)
After 12 weeks of therapy
Median recurrence-free (RFS) rate (adjuvant phase)
From surgery assessed up to 3 years

Secondary Outcome

Measure

Time Frame

Incidence of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) (neoadjuvant phase)
After 12 weeks of therapy
Change in the uptake on Positron emission tomography (PET)/computed tomography (CT) results
5.5 years after study enrollment begins

Enrollment

30

Conditions


Intervention

Intervention Type

Drug

Intervention Name


Description

Given IV

Arm Group Label

Arm A (vemurafenib, cobimetinib, atezolizumab)

Arm B (cobimetinib, atezolizumab)


Other Name

MPDL 3280A

MPDL 328OA

MPDL-3280A

MPDL3280A

MPDL328OA

RG7446

RO5541267

Tecentriq



Intervention Type

Drug

Intervention Name


Description

Given PO

Arm Group Label

Arm A (vemurafenib, cobimetinib, atezolizumab)

Arm B (cobimetinib, atezolizumab)


Other Name

Cotellic

GDC-0973

MEK Inhibitor GDC-0973

XL518



Intervention Type

Drug

Intervention Name


Description

Given PO

Arm Group Label

Arm A (vemurafenib, cobimetinib, atezolizumab)

Other Name

BRAF (V600E) kinase inhibitor RO5185426

BRAF(V600E) Kinase Inhibitor RO5185426

PLX-4032

PLX4032

RG 7204

RG7204

RO 5185426

Zelboraf




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.

Gender

All

Minimum Age

18 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Matthew Block
Principal Investigator
Mayo Clinic

Location

Facility

Status

Contact

Investigator

University of Minnesota/Masonic Cancer Center
Minneapolis Minnesota 55455 United States
Not yet recruiting
Last Name: Shernan G. Holtan, M.D.
Last Name: Shernan G. Holtan, M.D.
Role: Principal Investigator
Mayo Clinic
Rochester Minnesota 55905 United States
Recruiting
Last Name: Clinical Trials Referral Office
Phone: 855-776-0015
Last Name: Matthew S. Block, M.D., Ph.D.
Role: Principal Investigator

Location Countries

Country

United States


Verification Date

2018-08-01

Lastchanged Date

N/A

Firstreceived Date

N/A

Responsible Party

Responsible Party Type

Sponsor


Condition Browse


Secondary Id

NCI-2018-01018

MC1776

P30CA015083


Number Of Arms

2

Intervention Browse

Mesh Term

Atezolizumab

Vemurafenib

Antibodies, Monoclonal



Arm Group

Arm Group Label

Arm A (vemurafenib, cobimetinib, atezolizumab)

Arm Group Type

Experimental

Description

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.


Arm Group Label

Arm B (cobimetinib, atezolizumab)

Arm Group Type

Experimental

Description

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.



Firstreceived Results Date

N/A

Acronym

NeoACTIVATE

Other Outcome

Measure

Pretreatment soluble (s)PD-L1, pretreatment tumor PD-L1, and pretreatment intracellular Bim in tumor-related T cells

Time Frame

Up to 3 years

Description

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.


Measure

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

Description

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.



Firstreceived Results Disposition Date

N/A

Study Design Info

Allocation

Non-Randomized

Intervention Model

Parallel Assignment

Primary Purpose

Treatment

Masking

None (Open Label)


Study First Submitted

May 29, 2018

Study First Submitted Qc

June 11, 2018

Study First Posted

June 12, 2018

Last Update Submitted

August 14, 2018

Last Update Submitted Qc

August 14, 2018

Last Update Posted

August 16, 2018


ClinicalTrials.gov processed this data on August 16, 2018

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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