Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm
Conditions
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.
Interventions
PROCEDUREBiopsy Procedure
Undergo biopsy
PROCEDUREBiospecimen Collection
Undergo collection of blood samples
PROCEDUREComputed Tomography
Undergo CT
PROCEDUREEchocardiography Test
Undergo ECHO
OTHERElectronic Health Record Review
Undergo review of SOC RNA testing results
DRUGEnfortumab Vedotin
Given IV
OTHERImmunohistochemistry Staining Method
Undergo IHC assay
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
PROCEDUREMultigated Acquisition Scan
Undergo MUGA
BIOLOGICALSacituzumab Govitecan
Given IV
BIOLOGICALTrastuzumab Deruxtecan
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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). * Note: Patients with active metastatic disease that is not measurable but who are expected to be eligible for a Treatment Cohort can be screened after discussion with the primary investigator (PI) * Age ≥ 18 years. Because no dosing or adverse event (AE) data are currently available on the use of the Cancer Therapy Evaluation Program (CTEP) investigational new drug (IND) agents to be used in the study in patients \< 18 years of age, children are excluded from this study * Eastern Cooperative Oncology Group performance status of 0-2 based on most recent assessment (Karnofsky ≥ 50%) * No history of transfusion dependence * No history of persistent bone marrow suppression (absolute neutrophil count ≥ 1,500/mL and platelets ≥ 100,000/mL not attributable to active therapy; patients currently on bone marrow suppressive therapy can undergo assessment for the screening protocol but cannot be treated on any of the treatment cohorts unless bone marrow suppression is reversed off the suppressive therapy) (New testing will not be performed for the screening protocol, but rather existing labs will be assessed to assess eligibility) * Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is ≤ 3 × ULN (New testing will not be performed for the screening protocol, but rather existing labs will be assessed to assess eligibility) * Aspartate transaminase (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine transaminase (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 2.5 × institutional ULN. Transaminases up to 5 × ULN in the presence of liver metastases are not allowed to initiate the screening protocol but are allowed for the treatment cohorts (New testing will not be performed for the screening protocol, but rather existing labs will be assessed to assess eligibility) * Creatinine ≤ institutional ULN OR glomerular filtration rate ≥ 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m\^2 (New testing will not be performed for the screening protocol, but rather existing labs will be assessed to assess eligibility) * Patients must have albumin ≥ 3 g/dL * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational agents are eligible for this study * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this study, patients should be class 2B or better * Women of childbearing potential must not be known to be pregnant. Pregnancy testing is not required * Ability to understand and the willingness to sign a written informed consent document * ADDITIONAL INCLUSION CRITERIA FOR TREATMENT COHORTS: * Women of childbearing potential must have a negative serum pregnancy test result at treatment cohort screening * The effects of the study drugs on the developing human fetus are unknown. For this reason and because investigational agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after completion of study drug administration (unless otherwise indicated in the eligibility section \[Section 2\] of the Treatment Cohort protocols). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months after completion of study drug administration * Hemoglobin \> 9.0 g/dL * Leukocytes ≥ 3000/mL * Absolute neutrophil count ≥ 1,500/mL * Platelets ≥ 100,000/mL * Patient must be willing to sign the relevant treatment cohort consent form * Patients should have received no more than 3 prior lines of chemotherapy in the advanced/metastatic setting. Therapy given for only 1 cycle and discontinued because of toxicity in the absence of disease progression will not be counted as a line of therapy. Radio-sensitizing chemotherapy, if only given with radiation therapy will not be considered a line of therapy * Human immunodeficiency virus-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this study * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * COHORT A INCLUSION CRITERIA: * Patients must fulfill all the eligibility criteria outlined in the ADC MATCH screening protocol at the time of treatment cohort A registration * Patient must have high Trop-2 protein expression (IHC 2+ or 3+) as determined by the MD Anderson Cancer Center Clinical Laboratory Improvement Amendments IHC assay * Patients who have Trop-2 IHC testing without RNA testing or who have Trop-2 IHC 2 or 3+ expression but do not have Trop-2 expression detected on RNA testing will not be eligible for the trial. * Patients who have Trop-2 RNA expression and Trop-2 IHC 2+ or 3+ on another Trop-2 IHC test will undergo Trop-2 testing with the integral MDACC IHC assay * Patients who already have RNA expression testing demonstrating Trop-2 RNA expression as well as IHC testing on the MDACC CLIA lab platform will be eligible for enrollment after review of results by the Precision Oncology Decision Support team without having to repeat Trop-2 IHC results as part of pre-screening. Patients who have had TROP2 2+ testing result performed outside of MDACC will have to undergo MDACC TROP2 IHC analysis before enrollment * COHORT B INCLUSION CRITERIA: * Patients must fulfill all the eligibility criteria outlined in the ADC MATCH screening protocol at the time of treatment cohort B registration * Patient must have high Nectin-4 protein expression (IHC 2+ or 3+) as determined by the MD Anderson Cancer Center Clinical Laboratory Improvement Amendments IHC assay * COHORT C INCLUSION CRITERIA: * Patients must fulfill all the eligibility criteria outlined in the ADC MATCH screening protocol at the time of treatment cohort C registration * Patient must have HER2 protein expression (IHC 2+ or 3+) as determined by the MD Anderson Cancer Center (MDACC) IHC assay * Patients who have HER2 IHC testing without RNA testing or who have HER2 IHC 2 or 3+ expression but do not have HER2 expression detected on RNA testing will not be eligible for the trial * Patients who have HER2 RNA expression and HER2 IHC 3+ or 2+ on another HER2 IHC test will undergo HER2 testing with the integral MDACC IHC assay * Patients who already have RNA expression testing demonstrating HER2 RNA expression as well as IHC testing on the MDACC CLIA lab platform will be eligible for enrollment after review of results by the Precision Oncology Decision Support team without having to repeat HER2 IHC results as part of pre-screening. Patients who have had HER2 2+ testing result performed outside of MDACC will have to undergo MDACC HER2 IHC analysis before enrollment * Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 7 months after completion of study drug administration. Women should not breastfeed during the study treatment period and for 7 months after completion of study drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months after completion of study drug administration. Female patients must not donate, or retrieve for their own use, ova from the time of screening throughout the study treatment period and for at least 7 months after the final study drug administration. Female patients may wish to consider preservation of ova prior to enrollment in the study. Male patients should refrain from freezing or donating sperm during the study and for 6 months after the final study drug administration. Preservation of sperm should be considered prior to enrollment in the study * LVEF ≥50% within 28 days before enrollment
Exclusion criteria
* SCREENING PROTOCOL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (treatment cohorts) | 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. |
| Frequency of high protein expression in patients with high ribonucleic acid (RNA) expression of each antibody-drug conjugate target (screening protocol) | Up to completion of screening period | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Potential predictive biomarkers and other molecular features (treatment cohorts) | Up to 3 years | Logistic regression (or chi-squared test) or proportional hazard model (or log-rank test) will be used to identify potential predictive biomarkers, including target expression and other molecular features, for predicting response endpoints or survival endpoints. |
| Pharmacodynamic changes in the tumor and microenvironment (treatment cohorts) | Up to 3 years | — |
| Time to progression (treatment cohorts) | Up to 3 years | Will be estimated using the Kaplan-Meier method. |
| Incidence of adverse events (treatment cohorts) | Up to 30 days after completion of study treatment | Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. |
| 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 | Will be estimated using the Kaplan-Meier method. For each treatment cohort, 90% two-sided confidence intervals will be calculated for the proportion of patients alive and progression free at 6 months from start of cohort treatment. |
| RNA expression of targets of interest (TOIs) (treatment cohorts) | Up to 3 years | Pearson and Spearman correlation will be calculated to assess the correlation of RNA and protein expression of TOIs. |
| Overall survival (treatment cohorts) | From start of cohort treatment to time of death, assessed up to 3 years | Will be estimated using the Kaplan-Meier method. |
| Temporal tumor heterogeneity (treatment cohorts) | Up to 3 years | Paired t-test will be used to determine temporal tumor heterogeneity by comparing RNA/protein expression of TOIs on archival samples versus fresh biopsies. Graphic methods will be used to depict the temporal changes in RNA/protein expression of TOIs over time. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORFunda Meric-Bernstam
University of Texas MD Anderson Cancer Center LAO
Outcome results
None listed