Clinical trial NCT02091141: My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors
Official title: My Pathway: An Open-Label Phase IIa Study Evaluating Trastuzumab/Pertuzumab, Erlotinib, Vemurafenib/Cobimetinib, Vismodegib, Alectinib, and Atezolizumab in Patients Who Have Advanced Solid Tumors With Mutations or Gene Expression Abnormalities Predictive of Response to One of These Agents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neoplasms
Solid Tumors
Biliary Cancer
Salivary Cancer
Bladder Cancer
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2014-03-19
Enrollment: 673
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.


Eligibility criteria: General Inclusion Criteria:

* Life expectancy greater than or equal to (≥) 12 weeks
* Histologically documented metastatic cancer (solid tumors, not including hematologic malignancies)
* Participants who have received standard first-line therapy for metastatic cancer (except for the tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is considered the best available treatment option. Eligible participants should not have available therapies that will convey clinical benefit and/or are not suitable options per the treating physician's judgment
* No previous treatment with the specific assigned study drug or any other drug sharing the same target
* Measurable disease by RECIST v1.1
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 (For patients enrolling in the atezolizumab arm, ECOG score must be documented within 7 days prior to first treatment and confirmation of ECOG PS must be entered into the interactive web response system \[IWRS\] prior to initiation of treatment)
* Adequate hematologic, renal, and liver function as defined by the protocol
* If applicable, use of contraception methods or abstinence as defined by the protocol

Study-Drug Specific Inclusion Criteria:

Trastuzumab plus Pertuzumab

* Molecular testing results from clinical laboratory improvement amendments (CLIA)-certified laboratories (using tissue and/or blood) demonstrating HER2 overexpression or amplification. Participants must have one of the following tumor types: biliary cancer, salivary cancer, or bladder cancer

  a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)
* Left ventricular ejection fraction (LVEF) greater than (\>) 50 percent (%) or above the lower limit of the institutional normal range, whichever is lower
* Availability of an archival or new pre-treatment tissue sample is required if molecular testing was not performed by Foundation Medicine. Any available tumor tissue sample can be submitted. The tissue sample must be submitted within 4 weeks after enrollment

Erlotinib

* Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating epidermal growth factor receptor (EGFR)-activating mutations

Vemurafenib plus Cobimetinib

* Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating BRAF V600 mutations a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)

Vismodegib

* Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating hedgehog pathway relevant mutation (activating mutation of smoothened \[SMO\] or loss-of-function mutation of protein patched homolog-1 \[PTCH-1\])

  a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)
* All non-hematological adverse events related to any prior chemotherapy, surgery, or radiotherapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade less than or equal to (≤) 2 prior to starting therapy

Alectinib

* Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating anaplastic lymphoma kinase (ALK) gene rearrangements, ALK mutations, ALK copy number gain or (for melanoma only) increased ALK expression or presence of ALK-alternative transcription initiation transcript (ALKATI) a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)

Atezolizumab

* Molecular testing results from CLIA-certified laboratories (using tissue) demonstrating elevated tissue tumor mutational burden (tTMB ≥10 mutations/ Megabase \[Mb\])
* For patients where molecular testing was not performed using Foundation Medicine, submission of an archival or new pretreatment tissue sample is mandatory. For patients where molecular testing was performed using Foundation Medicine, submission of an archival or new pretreatment tissue sample is required, if available. The tissue sample must be submitted within 4 weeks after enrollment

General Exclusion Criteria:

* Participants with hematologic malignancies
* Concurrent administration of any other anti-cancer therapy (except male participants with prostate cancer receiving androgen blockade): Bisphosphonates and denosumab are allowed; Most recent anti-cancer therapy ≤28 days and have not recovered from the side effects, excluding alopecia; Radiation therapy within ≤14 days
* Active or untreated brain metastases
* History of carcinomatous meningitis
* Uncontrolled concurrent malignancy (early stage is allowed if not requiring active therapy or intervention)
* Pregnant or breastfeeding women, or intending to become pregnant during the study
* Any significant cardiovascular events within 6 months prior to study entry
* Pulmonary embolism within 30 days prior to study entry
* History or presence of clinically significant ventricular or atrial dysrhythmia \>Grade 2 per NCI CTCAE v4.0
* Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Study-Drug Specific Exclusion Criteria:

Trastuzumab plus Pertuzumab

* Previous treatment with any HER2-targeted therapy

Erlotinib

* Non-small cell lung cancer (NSCLC) or pancreatic cancer identified by exon 19 deletions or exon 21 L858R substitution mutations
* EGFR amplifications in the absence of EGFR-activating mutations
* Cancers with exon 20 mutations
* Previous treatment with erlotinib or any other EGFR inhibitor
* Inability to swallow pills
* Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of erlotinib

Vemurafenib plus Cobimetinib

* Malignant melanoma, papillary thyroid cancer, colorectal cancer, or hematologic malignancy including multiple myeloma
* LVEF below institutional lower level of normal (LLN) or below 50%, whichever is lower
* History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration
* Presence of any of the following conditions, which are risk factors for RVO: Uncontrolled glaucoma with intraocular pressure \>21 millimetres of mercury (mm Hg); Serum cholesterol ≥Grade 2; Hypertriglyceridemia ≥Grade 2; Hyperglycemia (fasting) ≥Grade 2; Grade ≥2 uncontrolled hypertension (participants with a history of hypertension controlled with anti-hypertensive medication to Grade \</=1 are eligible)
* Prior or concurrent malignancy with known RAS mutation
* Previous treatment with vemurafenib or any other BRAF inhibitor (prior sorafenib is allowed)
* Previous treatment with cobimetinib or any other mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor
* Prior treatment with a RAF inhibitor
* Inability to swallow pills
* Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of vemurafenib
* History of congenital long QT syndrome or mean (average of triplicate measurements) corrected QT (QTc) measured using Fridericia's method ≥450 millisecond (ms) at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus)

Vismodegib

* Basal cell carcinoma of the skin, medulloblastoma, small-cell lung cancer, or hematologic malignancies
* Previous treatment with vismodegib or any other hedgehog pathway inhibitor
* Inability to swallow pills
* Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of vismodegib

Alectinib

* ALK-positive NSCLC, neuroblastoma, and childhood tumors
* Previous treatment with alectinib or any other ALK inhibitor
* Participants with symptomatic bradycardia
* Administration of strong/potent cytochrome P3A4 (CYP3A4) inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment with alectinib
* Inability to swallow pills
* Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of alectinib

Atezolizumab

* History of leptomeningeal disease
* Uncontrolled tumor pain
* Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters are allowed
* Uncontrolled or symptomatic hypercalcemia
* Previous treatment with atezolizumab or another programmed death-1 (PD-1)/PD-L1 inhibitor
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells
* Known allergy or hypersensitivity to any component of the atezolizumab formulation
* Active or history of autoimmune disease or immune deficiency
* 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 computed tomography (CT) scan
* Positive human immunodeficiency virus (HIV) test, active hepatitis B virus (HBV) infection, active hepatitis C virus (HCV) infection or active tuberculosis
* Severe infection within 4 weeks prior to initiation of study treatment
* Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
* Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
* 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
* 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 or within 5 months after the final dose of atezolizumab
* History of other malignancy within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
* 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 participant at high risk from treatment complications
* Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies
* Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is longer) prior to randomization
* Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study

Primary outcomes:
measure: Percentage of Participants in All Tumor-Pathway Cohorts With Overall Response, as Assessed by the Investigator
timeFrame: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (72.1 months)
measure: Percentage of Atezolizumab-Treated Participants With Tissue Tumor Mutational Burden (tTMB) ≥16 Mutations/Mb With Overall Response, as Assessed by the Independent Review Committee (IRC)
timeFrame: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (68.9 months)
Secondary outcomes:
measure: Percentage of Participants With Disease Control
timeFrame: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (72.1 months)
measure: Progression-Free Survival (PFS)
timeFrame: From the date of first study treatment until disease progression as assessed by the investigator, or death from any cause, whichever occurs first (72.1 months)
measure: Overall Survival (OS)
timeFrame: 87.5 months
measure: Duration of Response (DoR)
timeFrame: From the date of first documented response (complete response [CR] or partial response [PR]) to the time of disease progression or death from any cause, whichever occurs first (70.8 months)
measure: Number of Participants With Adverse Events
timeFrame: From first study treatment administration to 30 days (45 days for vismodegib, 90 days for atezolizumab) after the last dose (up to approximately 6.3 years)
Other outcomes:
Locations:
city: Goodyear
country: United States
facility: Western Regional Medical Center at Cancer Treatment Centers of America
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Springdale
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Culver City
country: United States
facility: Science 37, Inc
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center; Dept Clinical Trials Office
state: California
city: Rancho Mirage
country: United States
facility: Eisenhower Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Comprehensive Cancer Center
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente - Vallejo
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Fort Myers
country: United States
facility: SCRI Florida Cancer Specialists South
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Inst; Memorial System Onc Clin Rsch
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialist, North Region
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists, Research Department
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center, LLC; Research
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center; Oncology Research Dept-5C
state: Georgia
city: Newnan
country: United States
facility: Southeastern Regional Medical Center, Inc.
state: Georgia
city: Chicago
country: United States
facility: Northwestern University; Robert H. Lurie Comp Can Ctr; Northwestern Medicine Development Inst
state: Illinois
city: Chicago
country: United States
facility: University Of Chicago Medical Center; Section Of Hematology/Oncology
state: Illinois
city: Zion
country: United States
facility: Midwestern Regional Med Center
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Rochester
country: United States
facility: Mayo Foundation
state: Minnesota
city: Kansas City
country: United States
facility: Research Medical Center - Antibiotic Research Associates, Inc.
state: Missouri
city: Middletown
country: United States
facility: Memorial Sloan Kettering - Monmouth
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Comprehensive Cancer Center
state: New Mexico
city: Albuquerque
country: United States
facility: University of New Mexico Comprehensive Cancer Center - Albuquerque Cedar Street; Drug Shipment
state: New Mexico
city: Albuquerque
country: United States
facility: University of New Mexico Comprehensive Cancer Center - Albuquerque Lang NE; Drug Shipment
state: New Mexico
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Farmington
country: United States
facility: San Juan Oncology Associates
state: New Mexico
city: Harrison
country: United States
facility: Memorial Sloan Kettering Cancer Center at Westchester
state: New York
city: New York
country: United States
facility: Weill Cornell Univ Medical Ctr; Breast Cancer Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center; Herbert Irving Pavillion
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: Univ No Carolina School of Med; Physicians Office Bldg
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Univ Health Svcs; Internal Medicine
state: North Carolina
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: Abramson Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Eastern Regional Medical Ctr
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC - Hillman Cancer Center
state: Pennsylvania
city: Willow Grove
country: United States
facility: Abington Mem Hosp-Abington; Rose. Can Ctr,Gyn Onc Ins
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Cancer Cnt Onco Clinic
state: South Dakota
city: Chattanooga
country: United States
facility: Sarah Cannon Research Institute / Tennessee Oncology
state: Tennessee
city: Germantown
country: United States
facility: West Clinic
state: Tennessee
city: Knoxville
country: United States
facility: Tennessee Cancer Specialists
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology - Nashville
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Clinic
state: Tennessee
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders - Fort Worth
state: Texas
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Richmond
country: United States
facility: Virginia Cancer Institute
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Narita Y, Yoshimoto T, Namai T, Asakawa T, Kawakami S, Gower-Page C, Reyes-Rivera I, Patel A, Nakamura Y. Pertuzumab Plus Trastuzumab for Treatment-Refractory HER2-Amplified Metastatic Colorectal Cancer: Comparison of the MyPathway Trial With a Real-World External Control Arm. JCO Clin Cancer Inform. 2022 May;6:e2200022. doi: 10.1200/CCI.22.00022.
citation: Friedman CF, Hainsworth JD, Kurzrock R, Spigel DR, Burris HA, Sweeney CJ, Meric-Bernstam F, Wang Y, Levy J, Grindheim J, Shames DS, Schulze K, Patel A, Swanton C. Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study. Cancer Discov. 2022 Mar 1;12(3):654-669. doi: 10.1158/2159-8290.CD-21-0450.
citation: Javle M, Borad MJ, Azad NS, Kurzrock R, Abou-Alfa GK, George B, Hainsworth J, Meric-Bernstam F, Swanton C, Sweeney CJ, Friedman CF, Bose R, Spigel DR, Wang Y, Levy J, Schulze K, Cuchelkar V, Patel A, Burris H. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021 Sep;22(9):1290-1300. doi: 10.1016/S1470-2045(21)00336-3. Epub 2021 Jul 30.
citation: Meric-Bernstam F, Hurwitz H, Raghav KPS, McWilliams RR, Fakih M, VanderWalde A, Swanton C, Kurzrock R, Burris H, Sweeney C, Bose R, Spigel DR, Beattie MS, Blotner S, Stone A, Schulze K, Cuchelkar V, Hainsworth J. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019 Apr;20(4):518-530. doi: 10.1016/S1470-2045(18)30904-5. Epub 2019 Mar 8.
citation: Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, Burris H, Bose R, Yoo B, Stein A, Beattie M, Kurzrock R. Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study. J Clin Oncol. 2018 Feb 20;36(6):536-542. doi: 10.1200/JCO.2017.75.3780. Epub 2018 Jan 10.