Optimizing Antibody-Drug Conjugate Therapy Through Molecular Analysis for Therapy Choice (ADC MATCH)
Overview
- Phase
- Phase 2
- Intervention
- Electronic Health Record Review
- Conditions
- Advanced Malignant Solid Neoplasm
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 500
- Locations
- 33
- Primary Endpoint
- Frequency of high protein expression in patients with high ribonucleic acid (RNA) expression of each antibody-drug conjugate target (screening protocol)
- Status
- Recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
This phase II ADC MATCH screening and multi-sub-study treatment trial is evaluating whether biomarker-directed treatment with one of three antibody-drug conjugates (ADCs) (sacituzumab govitecan, enfortumab vedotin, and trastuzumab deruxtecan) works in treating patients with solid tumor cancers that have high expression of the Trop-2, nectin-4, or HER2 proteins and that may have spread from where they first started (primary site) to nearby tissue, lymph nodes, or distant parts of the body (advanced) or to other places in the body (metastatic). Precision medicine is a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, or treat disease in a way that is tailored to the patient. ADCs such as sacituzumab govitecan, enfortumab vedotin, and trastuzumab deruxtecan are monoclonal antibodies attached to biologically active drugs and are a form of targeted therapy. Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a drug called govitecan. Sacituzumab attaches to a protein called Trop-2 on the surface of tumor cells and delivers govitecan to kill them. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of tumor cells. Enfortumab attaches to a protein called nectin-4 on tumor cells in a targeted way and delivers vedotin to kill them. Trastuzumab deruxtecan is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Personalized treatment with sacituzumab govitecan, enfortumab vedotin, or trastuzumab deruxtecan may be an effective treatment option for patients with advanced or metastatic solid tumors that screen positive for high expression of Trop-2, nectin-4, or HER2, respectively.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the proportion of patients with expression of targets of interest (TOIs) by ribonucleic acid (RNA) testing who have expression of the TOI protein by immunohistochemistry (IHC). (ADC MATCH screening protocol) II. To evaluate the objective response rate (ORR) of patients with advanced/metastatic solid tumors and high TOI protein expression to matched ADCs. (ADC MATCH treatment cohorts) SECONDARY OBJECTIVES: I. To determine the proportion of patients with high validated TOI protein expression who receive treatment on ADC MATCH. (ADC MATCH screening protocol) II. To evaluate the proportion of patients with advanced/metastatic solid tumors who are alive and progression free at 6 months of treatment with targeted ADC. (ADC MATCH treatment cohorts) III. To evaluate time until death or disease progression. (ADC MATCH treatment cohorts) IV. To determine progression-free survival (PFS) compared to prior line of therapy (PFS2/PFS1). (ADC MATCH treatment cohorts) V. To determine the correlation of RNA and protein expression of TOIs. (ADC MATCH treatment cohorts) VI. To determine temporal tumor heterogeneity by comparing RNA/protein expression of TOIs on archival samples versus fresh biopsies. (ADC MATCH treatment cohorts) VII. To identify potential predictive biomarkers, including target expression (RNA and protein) and other molecular features (deoxyribonucleic acid \[DNA\], RNA, protein, immune markers). (ADC MATCH treatment cohorts) VIII. To determine pharmacodynamic changes in the tumor and microenvironment. (ADC MATCH treatment cohorts) EXPLORATORY OBJECTIVE: I. To determine mechanisms of acquired resistance. (ADC MATCH treatment cohort) OUTLINE: SCREENING STEP 1: Patients who have previously undergone standard of care (SOC) RNA testing have the results of their SOC RNA testing reviewed. Patients whose tumor expresses an appropriate TOI by RNA testing proceed to screening step 2. SCREENING STEP 2: Patients have TOI expression testing at the protein level by IHC assay performed on previously collected tissue. Patients with high Trop-2 protein expression are assigned to Cohort A. Patients with high nectin-4 protein expression are assigned to Cohort B. Patients with high HER2 protein expression are assigned to cohort C. COHORT A: Patients receive sacituzumab govitecan-hziy intravenously (IV) over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression. COHORT B: Patients receive enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression. COHORT C: Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression. At the time that a confirmed objective response is observed for a specific tumor type in any cohort, that tumor type may be expanded into a separate tumor-specific expansion cohort, with up to 2 expansion cohorts allowed per treatment cohort. At the time of disease progression, patients with expression of additional TOIs may be re-screened and assigned to receive treatment in up to 2 of the other treatment cohorts. After completion of study treatment, patients are followed up at 30 days then every 3 months in years 1-2 and every 6 months in year 3.
Investigators
Eligibility Criteria
Inclusion Criteria
- •SCREENING PROTOCOL INCLUSION CRITERIA:
- •Patients must have histologically confirmed solid tumor requiring therapy and meet one of the following criteria:
- •Patients must have disease not amenable to curative-intent therapy AND
- •Patients who have had disease progression after treatment with all available therapies for their disease that are known to confer benefit or are intolerant to such treatment will be eligible, if other eligibility criteria are met. If the patient is currently receiving therapy without progression, the clinician must have assessed that the current therapy is no longer benefitting the patient, or that the patient is not tolerating the therapy. Patients can be screened on ADC MATCH if they have had three or fewer-lines of chemotherapy in the advanced/metastatic setting and are expected to need a treatment change within 6 months, and ADC MATCH is felt to be appropriate next line therapy AND
- •Patients with disease for which no standard treatment exists that has been shown to confer benefit OR
- •Patients who are willing to forego standard therapies known to confer benefit
- •NOTE: Patients can be on therapy at the time of initiating the Screening Protocol if the patient is interested in treatment on ADC MATCH upon progression, and the physician deems this appropriate
- •Patient must have undergone RNA testing in a Clinical Laboratory Improvement Act (CLIA) environment or must submit archival tissue to determine RNA overexpression of ADC TOIs by the TARGET Assay. Patients who have high TOI RNA expression will have confirmation of TOI expression by CLIA IHC assay at MD Anderson Cancer Center (MDACC). Only patients with confirmed TOI protein expression will be eligible for assignment to a treatment cohort. Retrospective confirmation in another central laboratory may also be performed. (A proportion of specimens in patients who are negative for RNA overexpression may be tested to better understand the concordance between the TARGET Assay and immunohistochemistry (IHC) assays, as funding and tissue availability allows. Only patients with RNA and protein expression with be eligible for treatment on ADC MATCH)
- •Patients must be willing to undergo mandatory pre-treatment and on-treatment tumor biopsies. Patients who do not consent to these research biopsies will not be eligible for prescreening. Patients who have screened and consented to a treatment cohort but are found to have disease that cannot be safely biopsied will be eligible for treatment provided all other eligibility criteria are met
- •Patients must have measurable disease. (Per radiologic imaging within the past 2 months).
Exclusion Criteria
- •SCREENING PROTOCOL EXCLUSION CRITERIA:
- •Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease. Patients with treated brain metastases are eligible if follow-up brain imaging 4 weeks after central nervous system-directed therapy shows no evidence of progression
- •Clinically significant cardiovascular condition including: (1) history of congestive heart failure (New York Health Association class \> 2), (2) any history of unstable angina, (3) myocardial infraction within the past 12 months, or (4) any history of supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention within the past 12 months
- •History or presence of abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful
- •Active or chronic corneal disorder including, but not limited to, Sjogren's syndrome, Fuchs corneal dystrophy (requiring treatment), history of corneal transplantation, active herpetic keratitis, and/or active ocular conditions requiring ongoing treatment/monitoring such as wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presence of papilledema, and acquired monocular vision
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to the ADCs used in the study
- •History of interstitial lung disease or pneumonitis requiring steroid therapy
- •Grade 2 or greater peripheral neuropathy
- •Patients requiring the use of full dose coumarin-derivative anticoagulants such as warfarin. Low molecular weight heparin is permitted for prophylactic or therapeutic use. Factor X inhibitors are permitted
- •Note: Warfarin may not be started while enrolled in the treatment cohorts. Stopping the anticoagulation for biopsy should be per site standard operating practice
Arms & Interventions
Screening (record review, IHC assay)
SCREENING STEP 1: Patients who have previously undergone SOC RNA testing have the results of their SOC RNA testing reviewed. Patients whose tumor expresses an appropriate TOI by RNA testing proceed to screening step 2. SCREENING STEP 2: Patients have TOI expression testing at the protein level by IHC assay performed on previously collected tissue. Patients with high Trop-2 protein expression are assigned to Cohort A. Patients with high nectin-4 protein expression are assigned to Cohort B. Patients with high HER2 protein expression are assigned to cohort C.
Intervention: Electronic Health Record Review
Screening (record review, IHC assay)
SCREENING STEP 1: Patients who have previously undergone SOC RNA testing have the results of their SOC RNA testing reviewed. Patients whose tumor expresses an appropriate TOI by RNA testing proceed to screening step 2. SCREENING STEP 2: Patients have TOI expression testing at the protein level by IHC assay performed on previously collected tissue. Patients with high Trop-2 protein expression are assigned to Cohort A. Patients with high nectin-4 protein expression are assigned to Cohort B. Patients with high HER2 protein expression are assigned to cohort C.
Intervention: Immunohistochemistry Staining Method
Cohort B (enfortumab vedotin)
Patients receive enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Computed Tomography
Cohort B (enfortumab vedotin)
Patients receive enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Magnetic Resonance Imaging
Cohort C (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Biopsy Procedure
Cohort C (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Magnetic Resonance Imaging
Cohort C (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Multigated Acquisition Scan
Cohort A (sacituzumab govitecan)
Patients receive sacituzumab govitecan-hizy IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Biopsy Procedure
Cohort A (sacituzumab govitecan)
Patients receive sacituzumab govitecan-hizy IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Biospecimen Collection
Cohort C (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Computed Tomography
Cohort A (sacituzumab govitecan)
Patients receive sacituzumab govitecan-hizy IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Sacituzumab Govitecan
Cohort B (enfortumab vedotin)
Patients receive enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Enfortumab Vedotin
Cohort A (sacituzumab govitecan)
Patients receive sacituzumab govitecan-hizy IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Computed Tomography
Cohort A (sacituzumab govitecan)
Patients receive sacituzumab govitecan-hizy IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Magnetic Resonance Imaging
Cohort B (enfortumab vedotin)
Patients receive enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Biopsy Procedure
Cohort B (enfortumab vedotin)
Patients receive enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Biospecimen Collection
Cohort C (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Biospecimen Collection
Cohort C (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Echocardiography Test
Cohort C (trastuzumab deruxtecan)
Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.
Intervention: Trastuzumab Deruxtecan
Outcomes
Primary Outcomes
Frequency of high protein expression in patients with high ribonucleic acid (RNA) expression of each antibody-drug conjugate target (screening protocol)
Time Frame: Up to completion of screening period
Objective response rate (treatment cohorts)
Time Frame: Up to 3 years
Will be defined as the proportion of patients who achieve complete response or partial response per the Response Evaluation Criteria in Solid Tumors version 1.1. For each treatment cohort, 90% two-sided confidence intervals will be calculated for objective response rate.
Secondary Outcomes
- Frequency that patients with high RNA and immunohistochemistry target expression receive cohort treatment on study (screening protocol)(Up to 3 years)
- Progression free survival (treatment cohorts)(From start of cohort treatment to time of progression or death, assessed at 6 months)
- Overall survival (treatment cohorts)(From start of cohort treatment to time of death, assessed up to 3 years)
- Time to progression (treatment cohorts)(Up to 3 years)
- Incidence of adverse events (treatment cohorts)(Up to 30 days after completion of study treatment)
- RNA expression of targets of interest (TOIs) (treatment cohorts)(Up to 3 years)
- Temporal tumor heterogeneity (treatment cohorts)(Up to 3 years)
- Potential predictive biomarkers and other molecular features (treatment cohorts)(Up to 3 years)
- Pharmacodynamic changes in the tumor and microenvironment (treatment cohorts)(Up to 3 years)