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Trilogy (CO39262)

AcronymISRCTNEudraCTClinicaltrials.govDRKS
CO392622016-002482-54

A phase III, double-blinded, randomized, Placebo-controlled study of Atezolizumab plus Cobimetinib and Vemurafenib versus Placebo plus Cobimetinib and Vemurafenib in previously untreated BRAF V600 mutation-positive patients with metastatic or unresectable locally advanced Melanoma.

Status: Active

Purpose / Objectives

Primary Outcome

Description of Study

Study CO39262 is a Phase III, double-blinded, placebo-controlled, randomized, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of atezo + cobi +vem compared with placebo + cobi + vem in patients with previously untreated BRAFV600 mutationpositive metastatic or unresectable locally advanced melanoma. The Primary endpoint of the study is progression-free survival (PFS).

Approximately 500 patients will be randomized in the study. Patients will be randomized in a 1:1 ratio to Arm A (placebo + cobi + vem) or Arm B (atezo + cobi + vem). Patients in both arms will be treated with cobimetinib and vemurafenib during a run-in period of 28 days. Patients in Arm A (control arm) will receive atezolizumab placebo, cobimetinib, and vemurafenib (960 mg twice daily [BID]). Patients in Arm B (experimental arm) will receive active atezolizumab, cobimetinib, and vemurafenib (720 mg BID). As the vemurafenib doses are different between in the two treatments arms, vemurafenib will be blinded in both study arms. To ensure adequate blinding, patients in both arms will receive the same number of vemurafenib tablets, with patients in Arm A receiving all active vemurafenib tablets and patients in Arm B receiving a combination of active vemurafenib tablets andvemurafenib placebo tablets.

Following randomization, patients will enter a 28-day run-in period to receive treatment with cobi + vem, followed by treatment with either atezo placebo + cobi + vem (Arm A) or atezo + cobi +vem+ vem placebo (Arm B) in the triple combination period. A stratified, permuted-block randomization scheme will be used for treatment allocation and will be based on the following stratification factors:

Geographic region (North America vs. Europe vs. Australia, New Zealand, and others)

Baseline LDH (the upper limit of normal [ULN] vs. >ULN) After signing informed consent, eligible patients will undergo screening procedures that include testing for the BRAFV600 mutation, laboratory tests, 12-lead ECGs, left ventricular function evaluation (echocardiogram or multigated acquisition scan), contrastenhanced brain computed tomography (CT) or magnetic resonance imaging (MRI), contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis, and ophthalmologic and dermatologic assessments.

All patients will be closely monitored for safety and tolerability throughout the study. The National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0 will be used to characterize the toxicity profile of the study treatments for all patients. The protocol includes a detailed risk management plan for monitoring and managing molecule-specific and potential combination toxicities. Tumor response will be evaluated by the investigator and by an independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Immune-Modified RECIST v1.1 will also be assessed by the IRC. All measurable and non-measurable lesions will be documented at screening. Response will be assessed by the investigator at 8- or 12-week intervals until investigator-determined disease Progression (according to RECIST v1.1), death, or initiation of subsequent anti-cancer therapy, whichever occurs first. Patients who experience disease progression must have scans repeated 48 weeks after initial documentation of progression to confirm disease progression. Tumor assessments are to continue according to schedule in patients who discontinue treatment for reasons other than confirmed disease progression, unless subsequent anti-cancer therapy is initiated.

Clinically stable patients who have a favorable benefit-risk ratio will continue on study Treatment following radiographic progression per RECIST v1.1. Patients who continue treatment beyond radiographic disease progression will be closely monitored. Treatment will be discontinued if clinical deterioration due to disease progression occurs at any time or if persistent disease growth is confirmed by follow-up scans performed 48 weeks later. Study treatment will continue for all patients until investigator-determined disease Progression (confirmed 48 weeks later, for clinically stable patients with a favorable benefit-risk ratio), death, unacceptable toxicity, or pregnancy, whichever occurs first. Patients who discontinue one study drug may be able to continue other study drugs, per guidelines for management of specific adverse events. After treatment discontinuation, patients will be followed for disease progression if applicable, and followed for survival until death, withdrawal of consent, or loss to follow-up, whichever occurs first.

Patients in the control arm are not eligible for crossover to the treatment arm at disease progression.

An independent Data Monitoring Committee (iDMC) will be employed to conduct periodic evaluations of safety data. All analyses for the iDMC’s review will be prepared by an independent Data Coordinating Center. Sponsor personnel will not have access to by-arm data summaries or listings prior to the formal reporting of the primary efficacy results. Specific details, including responsibilities and structure of the iDMC, will be specified in the iDMC charter.

Number of Patients Approximately 500 patients with previously untreated, BRAFV600 mutationpositive metastatic melanoma will be randomized in the study.

 

 

Diagnosis

A PHASE III, DOUBLE-BLINDED, RANDOMIZED,

PLACEBO-CONTROLLED STUDY OF

ATEZOLIZUMAB PLUS COBIMETINIB AND

VEMURAFENIB VERSUS PLACEBO PLUS

COBIMETINIB AND VEMURAFENIB IN

PREVIOUSLY UNTREATED BRAFV600

MUTATIONPOSITIVE PATIENTS WITH

METASTATIC OR UNRESECTABLE LOCALLY

ADVANCED MELANOMA

 

Patient attributes

Age

18-

Inclusion criteria

Inclusion Criteria

Patients must meet the following criteria for study entry:

  • Signed Informed Consent Form
  • Age ≥ 18 years
  • Able to comply with the study protocol, in the investigator’s judgment
  • Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma, as defined by the American Joint Committee on Cancer, 7th revised edition
  • Naïve to prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies), with the following exceptions:

Adjuvant treatment with interferon, interleukin-2, or vaccine therapies, if discontinued at least 28 days prior to initiation of study treatment

Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to initiation of study treatment

  • Documentation of BRAFV600 mutation−positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority (e.g., U.S. Food and Drug Administration-approved test, CE-marked [European conformity] in vitro diagnostic in E.U. countries, or equivalent) A representative, formalin-fixed, paraffin-embedded tumor specimen in a paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study entry. If archival tumor tissue is unavailable or is determined to be inadequate, tumor tissue must be obtained from a biopsy performed at screening.
  • Eastern Cooperative Oncology Group Performance Status of 0 or 1
  • Measurable disease according to RECIST v1.1
  • Willingness to undergo tumor biopsies of accessible lesions during treatment and at progression for exploratory biomarker analyses
  • Life expectancy ≥ 18 weeks
  • Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment

ANC ≥ 1.5 × 109/L without granulocyte colony-stimulating factor support

WBC count ≥2.5 × 109/L

Lymphocyte count ≥0.5 × 109/L

Platelet count ≥100 × 109/L without transfusion

Hemoglobin ≥90 g/L without transfusion

Serum albumin ≥25 g/L

Total bilirubin ≤1.5 × ULN

AST and ALT ≤2.0 × ULN

Alkaline phosphatase (ALP) ≤2.5 × ULN or, for patients with documented liver or bone metastases, ALP 5 × ULN

 Serum creatinine ≤ 1.5 × 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:

 CrCl = (140 − age) × (weight in kg)

 72 × (serum creatinine in mg/dL)

 (× 0.85 if female)

  • For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN within 28 days prior to initiation of study treatment
  • For patients receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment
  • For women 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

A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit Ovulation, hormone−releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study treatment to avoid exposing the embryo.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

 

 

Exclusion criteria

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from study entry:

Cancer-Related Exclusion Criteria:

Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study

Traumatic injury within 2 weeks prior to initiation of study treatment

Palliative radiotherapy within 14 days prior to initiation of study Treatment

  • Active malignancy (other than BRAFV600 mutation−positive melanoma) or malignancy within 3 years prior to screening, with the exception of resected melanoma, resected basal cell carcinoma, resected cutaneous squamous cell carcinoma, resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or other curatively treated malignancies from which the patient has been disease-free for at least 3 years

Patients with a history of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.

Ocular Exclusion Criteria:

  • History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration

Patients will be excluded from study participation if they currently are known to have any of the following risk factors for RVO:

Glaucoma with intraocular pressure ≥ 21 mmHg

Grade ≥ 2 serum cholesterol

Grade ≥ 2 hypertriglyceridemia

Grade ≥ 2 or symptomatic hyperglycemia (fasting)

Grade ≥ 2 uncontrolled hypertension (patients with a history of Hypertension controlled with anti-hypertensive medication to Grade ≤ 1 are eligible)

Cardiac Exclusion Criteria

  • History of clinically significant cardiac dysfunction, including the following:

Unstable angina, or new-onset angina within 3 months prior to initiation of study treatment

Symptomatic congestive heart failure, defined as New York Heart Association Class II or higher

Myocardial infarction within 3 months prior to initiation of study treatment

Unstable arrhythmia

History of congenital long QT syndrome

Mean (average of triplicate measurements) QTc interval corrected using Fridericia’s method ≥ 450 ms at screening, or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, and phosphorus)

Left ventricular ejection fraction below the institutional lower limit of normal or below 50%, whichever is lower

Central Nervous System Exclusion Criteria:

  • Untreated or actively progressing CNS lesions (carcinomatous meningitis)

Patients with a history of CNS lesions are eligible, provided that all of the following criteria are met:

Measurable disease, per RECIST v1.1, must be present outside the CNS.

All known CNS lesions have been treated with radiotherapy or surgery.

CNS lesions have not been treated with whole-brain radiotherapy, except in patients who underwent definitive resection of or stereotactic therapy for all radiologically detectable parenchymal brain lesions.

Absence of interim progression must be confirmed by radiographic study within 4 weeks prior to initiation of study treatment. If new CNS metastases are suspected during the screening period, a confirmatory radiographic study is required prior to initiation of study treatment.

Any radiotherapy or surgery must be completed ≥ 4 weeks prior to initiation of study treatment.

There is no ongoing requirement for corticosteroids, and any prior corticosteroid treatment must be discontinued ≥ 2 weeks prior to initiation of study treatment.Treatment with an anticonvulsant at a stable dose is allowed.

  • History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm)
  • History of leptomeningeal metastatic disease
  • History of intracranial hemorrhage

Additional Exclusion Criteria

  • Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) other than cancer
  • Anticipated use of any concomitant medication during or within 7 days prior to initiation of study treatment that is known to cause QT prolongation (which may lead to torsades de pointes)
  • Any psychological, familial, sociological, or geographical condition that may hamper compliance with the protocol and follow-up after treatment discontinuation
  • History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment
  • Pregnant or breastfeeding, or intending to become pregnant during the study

Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.

  • Prior allogeneic stem cell or solid organ transplantation
  • 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 History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  • History of autoimmune disease

Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for the study after discussion with and approval by the Medical Monitor.

Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for the study after discussion with and approval by the Medical Monitor.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

Rash must cover < 10% of body surface area

Disease is well controlled at baseline and requires only low-potency topical corticosteroids

No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months

  • Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease including:

Positive HIV test at screening

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at Screening Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible for the

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test and a positive HCV RNA test at screening

  • Active tuberculosis
  • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Signs or symptoms of infection within 2 weeks prior to initiation of study treatment
  • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from Treatment complications
  • Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment

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

  • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
  • Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study

Patients who have received acute, low-dose systemic immunosuppressant medication (10 mg/day oral prednisone or equivalent) 4 weeks prior to initiation of study treatment 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. 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 adrenocorticol insufficiency is allowed.

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells

Known hypersensitivity to any component of the atezolizumab, cobimetinib, or vemurafenib formulations

History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

Treatment with any other investigational agent or participation in another clinical study with therapeutic intent

Inability or unwillingness to swallow pills

Requirement for concomitant therapy or food that is prohibited during the study

 

 

Trial design

  • Phase III
  • Multicenter
  • Randomized
  • Two-arm
  • Double-blind
  • Placebo-controlled

Documents (password protected)

Responsibilities in overall trial

F. Hoffmann-La Roche AG

    National Coordinating Investigator

    Pr. Doz. Dr. med. Ralf Gutzmer

    Study Sites

    Klinik & Poliklinik für Dermatologie & Venerologie Köln

    Study office

    Status

    Active

    Principal Investigator

    PD Dr. med. Max Schlaak

    Deputy of Principal Investigator

    • Univ.-Prof. Dr. med. Dr. Cornelia Mauch

    Subinvestigator

    • Bodo Bühler
    • Dr. Nicole Kreuzberg
    • Sarah Ramesh

    Contact at Site