Targeted Therapy Directed by Genetic Testing in Treating Patients With Locally Advanced or Advanced Solid Tumors, The ComboMATCH Registration Trial
Study Details
Study Description
Brief Summary
This ComboMATCH registration trial studies how well treatment that is directed by genetic testing works in treating patients with solid tumors that have spread to nearby tissue or lymph nodes (locally advanced) or have spread to other places in the body (advanced) and have progressed on at least one line of standard systemic therapy or have no standard treatment that has been shown to prolong overall survival. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit more from treatment which targets their tumor's particular genetic mutation, and may help doctors plan better treatment for patients with locally advanced or advanced solid tumors.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- To register, allocate, and assign patients to ComboMATCH treatment trials.
SECONDARY OBJECTIVES:
-
To evaluate the rate of positive outcomes in defined cohorts within treatment trials of treatment combinations including targeted therapies for molecularly defined populations, and also in the subset of treatment trials where the treatments are supported by in vivo models.
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To perform quality control of the patients registered in the form of pathological confirmation of disease and sub-type to confirm diagnosis and treatment arm allocation.
SECONDARY CORRELATIVE OBJECTIVES:
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Assess the concordance of the central molecular characterization of the pre-treatment biopsy samples with the genetic readouts from the Designated Laboratories (DLs) for patients enrolled on the ComboMATCH treatment trials.
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To assess how the registration diagnostic tumor mutation profile and pre-treatment biopsy profile compare to the circulating tumor-derived deoxyribonucleic acid (ctDNA) mutation profile from plasma.
EXPLORATORY OBJECTIVE:
- Assess association between ComboMATCH treatment trials outcomes (positive or negative) with the type of rationale for the selected drug combinations and the type of rationale for the gene variant/combination for selection (e.g., whether the trial was based on targeted therapies for molecularly defined populations, those that were supported by in vivo models, and those that were supported by empiric clinical data).
OUTLINE:
REGISTRATION: Patients undergo tumor mutational screening of previously-collected tumor samples for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing. Patients who are 18 years or older and have biopsiable disease undergo a new biopsy for research purposes prior to initiating treatment on the ComboMATCH treatment trial.
TREATMENT: Patients with mutations targeted to investigational combination therapies are assigned to 1 of 20 treatment subprotocols.
EAY191-N4: Patients with RAS pathway mutant ovarian or endometrial cancer are randomized to 1 of 2 arms.
ARM I: Patients receive selumetinib orally (PO) and olaparib PO throughout the trial. Patients also undergo a tumor biopsy during screening and on study, blood collection during screening and on study, as well as computed tomography (CT) scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.
ARM II: Patients receive selumetinib PO throughout the trial. Patients who experience progression may elect to cross over to Arm I provided they have not had dose limiting toxicities to monotherapy selumetinib. Patients undergo a tumor biopsy during screening and during follow-up, blood collection during and on study, as well as CT scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.
EAY191-N2: Patients with NF1 nonsense or frameshift mutations or NF1 gene deletion, and hormone receptor positive, HER2-negative metastatic breast cancer. Patients who are fulvestrant naive are assigned to Cohort I, while patients who are fulvestrant resistant are assigned to Cohort II.
COHORT I: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive fulvestrant intramuscularly (IM) and binimetinib PO throughout the trial. Patients also undergo a CT, magnetic resonance imaging (MRI), or bone scan and tumor biopsy during screening and on study.
ARM II: Patients receive fulvestrant IM throughout the trial. Patients who progress on fulvestrant alone are asked to reaffirm their willingness to enroll in cohort II. Patients not willing to transition to cohort II continue further therapy as clinically indicated. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study.
COHORT II: Patients receive fulvestrant IM and binimetinib PO throughout the trial. If the patient progressed on fulvestrant, the loading dose of fulvestrant is omitted. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study.
EAY191-E4: Patients with solid tumors who previously underwent taxane therapy.
Patients receive nilotinib hydrochloride monohydrate PO and paclitaxel IV throughout the trial. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study.
EAY191-A3: Patients with KRAS/NRAS/BRAF mutated low-grade serous ovarian cancer (LGSOC) naive to MEK or CDK4/6 inhibitor therapy are randomized to either combination cohort 1 or monotherapy cohort 1. Patients with LGSOC who have received prior MEK inhibitor therapy are assigned to combination cohort 2. Patients with KRAS/NRAS/HRAS/non-V600E BRAF mutated pancreatic cancer are assigned to combination cohort 3. Patients with all other KRAS/NRAS/HRAS mutated tumor types (excluding LGSOC, non-small cell lung cancer, colorectal cancer, pancreatic, and melanoma) are assigned to combination cohort 4.
COMBINATION COHORTS 1, 2, 3, 4: Patients receive palbociclib PO and binimetinib PO throughout the trial. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up.
MONOTHERAPY COHORT 1: Patients receive binimetinib PO throughout the trial. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up.
EAY191-S3: Patients with an activating AKT mutation solid tumor.
Patients receive paclitaxel IV and ipatasertib PO throughout the trial. Patients undergo a CT or MRI and blood collection during screening, on study, and during follow-up. Patients also undergo a tumor biopsy during screening and follow-up.
EAY191-A6: Patients with RAS/RAF/MEK/ERK mutant biliary tract cancers are randomized to 1 of 2 arms.
ARM 1: Patients receive leucovorin IV, oxaliplatin IV, and fluorouracil IV on study. Patients undergo echocardiogram (ECHO) and multigated acquisition scan (MUGA) during screening and on study, a CT with contrast, MRI, or a fludeoxyglucose F-18 positron emission tomography (FDG-PET) during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated.
ARM 2: Patients receive binimetinib PO, leucovorin IV, oxaliplatin IV, and fluorouracil IV on study. Patients undergo ECHO and MUGA during screening and on study, a CT with contrast, MRI, or an FDG-PET during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated
EAY191-E5: Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients who have never received a KRAS G12C inhibitor randomized to arms A or B.
ARM A: Patients receive sotorasib PO and panitumumab IV on study. Patients also undergo collection of blood samples and a tumor biopsy before treatment and CT or MRI at follow up.
ARM B: Patients receive sotorasib PO on study. Patients with disease progression may cross-over to cohort II. Patients also undergo collection of blood samples and a tumor biopsy before treatment and CT or MRI at follow up.
COHORT II: Patients who have received a KRAS G12C inhibitor assigned to arm C.
ARM C: Patients receive combination therapy as in Arm A.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: EAY191-A3 Combo Cohorts 1, 2, 3, 4 (palbociclib, binimetinib) Patients receive palbociclib PO and binimetinib PO throughout the trial. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Scan
Undergo bone scan
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Drug: Palbociclib
Given PO
Other Names:
|
| Experimental: EAY191-A3 Monotherapy Cohort 1 (binimetinib) Patients receive binimetinib PO throughout the trial. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up. |
Drug: Binimetinib
Given PO
Other Names:
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Scan
Undergo bone scan
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
|
| Experimental: EAY191-A6 Arm I (RAS/RAF/MEK/ERK mutations) Patients receive leucovorin IV, oxaliplatin IV, and fluorouracil IV on study. Patients undergo ECHO and MUGA during screening and on study, a CT with contrast, MRI, or a FDG-PET during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Scan
Undergo bone scan
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Echocardiography
Undergo ECHO
Other Names:
Drug: Fluorouracil
Given IV
Other Names:
Drug: Leucovorin
Given IV
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Procedure: Multigated Acquisition Scan
Undergo MUGA
Other Names:
Drug: Oxaliplatin
Given IV
Other Names:
Procedure: Positron Emission Tomography
Undergo PET
Other Names:
|
| Experimental: EAY191-A6 Arm II (RAS/RAF/MEK/ERK mutations) Patients receive binimetinib PO, leucovorin IV, oxaliplatin IV, and fluorouracil IV on study. Patients undergo ECHO and MUGA during screening and on study, a CT with contrast, MRI, or an FDG-PET during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated |
Drug: Binimetinib
Given PO
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Scan
Undergo bone scan
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Echocardiography
Undergo ECHO
Other Names:
Drug: Fluorouracil
Given IV
Other Names:
Drug: Leucovorin
Given IV
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Procedure: Multigated Acquisition Scan
Undergo MUGA
Other Names:
Drug: Oxaliplatin
Given IV
Other Names:
Procedure: Positron Emission Tomography
Undergo PET
Other Names:
|
| Experimental: EAY191-E4 (taxane therapy) Patients receive nilotinib hydrochloride monohydrate PO and paclitaxel IV throughout the trial. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Drug: Nilotinib Hydrochloride Monohydrate
Given PO
Other Names:
Drug: Paclitaxel
Given PO or IV
Other Names:
|
| Active Comparator: EAY191-E5 Cohort I Arm B (panitumumab) Patients receive sotorasib PO on study. Patients with disease progression may cross-over to cohort II. Patients also undergo collection of blood samples and a tumor biopsy before treatment and CT or MRI at follow up. |
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Biological: Panitumumab
Given IV
Other Names:
|
| Experimental: EAY191-E5 Cohort I Arm I (sotorasib, panitumumab) Patients receive sotorasib PO and panitumumab IV on study. Patients also undergo collection of blood samples and a tumor biopsy before treatment and CT or MRI at follow up. |
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Biological: Panitumumab
Given IV
Other Names:
Drug: Sotorasib
Given PO
Other Names:
|
| Experimental: EAY191-E5 Cohort II (sotorasib) Patients receive combination therapy as in EAY191-E5 Arm A. |
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Biological: Panitumumab
Given IV
Other Names:
Drug: Sotorasib
Given PO
Other Names:
|
| Experimental: EAY191-N2 Cohort I (Arm I) (NF1 mutations) Patients receive fulvestrant IM and binimetinib PO throughout the trial. Patients also undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study. |
Drug: Binimetinib
Given PO
Other Names:
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Bone Scan
Undergo bone scan
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Drug: Fulvestrant
Given IM
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
|
| Experimental: EAY191-N2 Cohort I (Arm II) (NF1 mutations) Patients receive fulvestrant IM throughout the trial. Patients who progress on fulvestrant alone are asked to reaffirm their willingness to enroll in cohort II. Patients not willing to transition to cohort II continue further therapy as clinically indicated. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Bone Scan
Undergo bone scan
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Drug: Fulvestrant
Given IM
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
|
| Experimental: EAY191-N2 Cohort II (NF1 mutations) Patients receive fulvestrant IM and binimetinib PO throughout the trial. If the patient progressed on fulvestrant, the loading dose of fulvestrant is omitted. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study. |
Drug: Binimetinib
Given PO
Other Names:
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Bone Scan
Undergo bone scan
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Drug: Fulvestrant
Given IM
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
|
| Experimental: EAY191-N4 Arm I (RAS pathway mutations) Patients receive selumetinib PO and olaparib PO throughout the trial. Patients also undergo a tumor biopsy during screening and on study, blood collection during screening and on study, as well as CT scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Marrow Aspiration
Undergo bone marrow aspiration
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Mutation Carrier Screening
Undergo tumor mutational screening
Drug: Olaparib
Given PO
Other Names:
Drug: Selumetinib Sulfate
Given PO
Other Names:
|
| Experimental: EAY191-N4 Arm II (RAS pathway mutations) Patients receive selumetinib PO throughout the trial. Patients who experience progression may elect to cross over to Arm I provided they have not had dose limiting toxicities to monotherapy selumetinib. Patients undergo a tumor biopsy during screening and during follow-up, blood collection during and on study, as well as CT scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
Procedure: Bone Marrow Aspiration
Undergo bone marrow aspiration
Procedure: Computed Tomography
Undergo CT
Other Names:
Procedure: Mutation Carrier Screening
Undergo tumor mutational screening
Drug: Selumetinib Sulfate
Given PO
Other Names:
|
| Experimental: EAY191-S3 (activating AKT mutation) Patients receive paclitaxel IV and ipatasertib PO throughout the trial. Patients undergo a CT or MRI and blood collection during screening, on study, and during follow-up. Patients also undergo a tumor biopsy during screening and follow-up. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Drug: Ipatasertib
Given PO
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Drug: Paclitaxel
Given PO or IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Accrual of patients to ComboMATCH treatment trials [Up to 8 years]
Will be estimated over time and considered in relationship to changes in treatment trial cohort status (activations, suspensions, terminations).
- Assignment of patients to ComboMATCH treatment trials [Up to 8 years]
Will be estimated over time and considered in relationship to changes in treatment trial cohort status (activations, suspensions, terminations).
- Enrollment rates to ComboMATCH treatment trials [Up to 8 years]
Will be estimated over time and considered in relationship to changes in treatment trial cohort status (activations, suspensions, terminations).
Secondary Outcome Measures
- Rate of positive outcomes within the treatment trial defined cohorts [Up to 8 years]
For each cohort in each treatment trial there is a defined primary efficacy endpoint (usually progression free survival [PFS] or overall response rate) and defined primary analysis for evaluating the primary endpoint. As cohorts are completed, whether they meet the criteria for a positive primary outcome will be determined. Positive treatment cohort outcome (on primary endpoint) will be analyzed as a binary random variable. The raw proportion of treatment cohorts with positive outcomes and an exact binomial confidence interval will be computed. If there are a sufficient number of treatment cohorts, logistic regression analysis will be performed examining the relationship of treatment cohort characteristics with successful outcomes. The goal is to achieve a rate of at least 30% with positive outcomes, both overall and in the subset of treatment trials based on in vivo models.
Other Outcome Measures
- Concordance between whole exome sequencing (WES) and results from the Designated Laboratory (DL) [Up to 8 years]
Whole exome and other sequencing will be performed on mandatory tissue biopsies or, if no biopsy tissue is available, on submitted formalin-fixed paraffin-embedded tissue. These assays will be done in a clinical laboratory (e.g., Clinical Laboratory Improvement Act-compliant); but results will not be returned to the clinical site. Results will be used to compare with the DL assay results. This comparison will be required to conduct an important secondary analysis of the primary endpoint in each cohort in each treatment trial, restricting to those cases that are concordant between WES and the result from the DL that was the basis for enrollment (integrated).
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patient must have measurable disease
-
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 OR patient must have Lansky performance status of >= 50% or Karnofsky performance status of >= 50%
-
Patient must be deemed potentially eligible for a ComboMATCH Treatment Trial as assessed by the enrolling provider
-
All patients must have sequencing results available from a National Cancer Institute (NCI) credentialed Designated Laboratory (DL)
-
Patients must have locally advanced or advanced histologically documented solid tumors requiring therapy and meet one of the following criteria:
-
Patients must have progressed on at least one line of standard systemic therapy OR
-
Patients whose disease has no standard treatment that has been shown to prolong overall survival
-
Patient must meet one of the following requirements:
-
Patients 18 years and older who have tumor amenable to minimal risk image-guided or direct vision biopsy and must be willing and able to undergo a tumor biopsy to obtain samples for research if the patient is to enroll in a ComboMATCH treatment trial OR
-
Patients 18 years and older who do not have disease that is biopsiable at minimal risk to the patient must confirm availability of an archival tumor tissue specimen for submission for research if the patient enrolls to a ComboMATCH
Treatment Trial. This tumor tissue must meet the following criteria:
-
Tissue must have been collected within 12 months prior to registration to the EAY191 Registration Trial
-
Patient must not have had a Response Evaluation Criteria in Solid Tumors (RECIST) response (complete response [CR] or partial response [PR]) to any intervening therapy after collection of the tissue
-
Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available OR
-
Patients under 18 years old must confirm availability of an archival tumor tissue specimen for submission for research if patient enrolls to a ComboMATCH Treatment
Trial. This tumor tissue must meet the following criteria:
-
Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available
-
NOTE: See specific ComboMATCH Treatment Trial protocol for tissue collection and management instructions. Performance of the mandatory research biopsy or submission of pre-trial formalin-fixed paraffin-embedded (FFPE) and collection and submission of the blood specimens for the integrated studies will be performed under the consent authority of the specific treatment trial protocol to which the patient is registered. No procedures to collect specimens for research only are to be performed for patients registered to the EAY191 Registration Trial only
-
NOTE: Each ComboMATCH Treatment Trial contains specific eligibility criteria. If patient is found to not be eligible for the assigned ComboMATCH Treatment Trial, indication of ineligibility will trigger re-evaluation and potential assignment to another Treatment Trial
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: James M Ford, ECOG-ACRIN Cancer Research Group
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2022-06842
- NCI-2022-06842
- EAY191
- EAY191
- U10CA180820