Personalized Antibody-Drug Conjugate Therapy Based on RNA and Protein Testing for the Treatment of Advanced or Metastatic Solid Tumors (The ADC MATCH Screening and Treatment Trial)

Inclusion Criteria:

• SCREENING PROTOCOL INCLUSION CRITERIA:

• Patients must have histologically confirmed solid tumor requiring therapy and meetone of the following criteria:

• Patients must have disease not amenable to curative-intent therapy OR

• Patients who have had disease progression after treatment with all availabletherapies for their disease that are known to confer benefit or are intolerantto such treatment will be eligible, if other eligibility criteria are met. Ifthe patient is currently receiving therapy without progression, the clinicianmust have assessed that the current therapy is no longer benefitting thepatient, or that the patient is not tolerating the therapy. Patients can bescreened on ADC MATCH if they are on first-line treatment and expected to needa treatment change within 3 months, and ADC MATCH is felt to be appropriatenext line therapy OR

• Patients with disease for which no standard treatment exists that has beenshown 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 ScreeningProtocol if the patient is interested in treatment on ADC MATCH uponprogression, and the physician deems this appropriate

• Patient must have undergone RNA testing in a Clinical Laboratory Improvement Act (CLIA) environment. Patients who have high TOI RNA expression will have confirmationof TOI expression by CLIA IHC assay at MD Anderson Cancer Center (MDACC). Onlypatients with confirmed TOI protein expression will be eligible for assignment to atreatment cohort. Retrospective confirmation in another central laboratory may alsobe performed

• Patients must be willing to undergo mandatory pre-treatment and on-treatment tumorbiopsies. Patients who do not consent to these research biopsies will not beeligible for prescreening. Patients who have screened and consented to a treatmentcohort but are found to have disease that cannot be safely biopsied will be eligiblefor treatment provided all other eligibility criteria are met

• Patients must have measurable disease

• Age ≥ 18 years. Because no dosing or adverse event (AE) data are currently availableon 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 areexcluded from this study

• Eastern Cooperative Oncology Group performance status of 0-2 (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; patientscurrently on bone marrow suppressive therapy can undergo assessment for thescreening protocol but cannot be treated on any of the treatment cohorts unless bonemarrow suppression is reversed off the suppressive therapy)

• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). Documented Gilbertsyndrome is allowed if total bilirubin is ≤ 3 × ULN

• Aspartate transaminase (serum glutamic-oxaloacetic transaminase [SGOT])/alaninetransaminase (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 × institutionalULN. Transaminases up to 5 × ULN in the presence of liver metastases are not allowedto initiate the screening protocol but are allowed for the treatment cohorts

• Creatinine ≤ institutional ULN OR glomerular filtration rate ≥ 60 mL/min/1.73 m^2for patients with creatinine levels above institutional normal unless data existssupporting safe use at lower kidney function values, no lower than 30 mL/min/1.73m^2

• Patients must have albumin ≥ 3 g/dL

• Human immunodeficiency virus-infected patients on effective anti-retroviral therapywith undetectable viral load within 6 months are eligible for this study

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational agents are eligible for this study

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this study, patients should be class 2B or better

• Women of childbearing potential must have a negative human serum pregnancy testresult at the screening protocol

• The effects of the study drugs on the developing human fetus are unknown. For thisreason and because investigational agents as well as other therapeutic agents usedin this trial are known to be teratogenic, women of childbearing potential and menmust agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry, for the duration of study participation,and for 6 months after completion of study drug administration (unless otherwiseindicated in the eligibility section of the treatment cohort protocols). Should awoman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to study entry, for the duration of study participation, and for 6 months after completion of study drug administration

• Ability to understand and the willingness to sign a written informed consentdocument

• ADDITIONAL INCLUSION CRITERIA FOR TREATMENT COHORTS:

• Women of childbearing potential must have a negative serum pregnancy test result attreatment cohort screening

• 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

• COHORT A INCLUSION CRITERIA:

• Patients must fulfill all the eligibility criteria outlined in the ADC MATCHscreening protocol at the time of treatment cohort A registration

• Patient must have high Trop-2 protein expression (IHC 2+ or 3+) as determined by theMD 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 testingwill not be eligible for the trial.

• Patients who have Trop-2 RNA expression and Trop-2 IHC 2+ or 3+ on anotherTrop-2 IHC test will undergo Trop-2 testing with the integral MDACC IHC assay

• Patients who already have RNA expression testing demonstrating Trop-2 RNAexpression as well as IHC testing on the MDACC CLIA lab platform will beeligible for enrollment after review of results by the Precision OncologyDecision Support team without having to repeat Trop-2 IHC results as part ofpre-screening. Patients who have had TROP2 2+ testing result performed outsideof 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 MATCHscreening protocol at the time of treatment cohort B registration

• Patient must have high Nectin-4 protein expression (IHC 2+ or 3+) as determined bythe 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 MATCHscreening protocol at the time of treatment cohort C registration

• Patient must have HER2 protein expression (IHC 2+ or 3+) as determined by the MDAnderson Cancer Center (MDACC) IHC assay

• Patients who have HER2 IHC testing without RNA testing or who have HER2 IHC 2or 3+ expression but do not have HER2 expression detected on RNA testing willnot be eligible for the trial

• Patients who have HER2 RNA expression and HER2 IHC 3+ or 2+ on another HER2 IHCtest will undergo HER2 testing with the integral MDACC IHC assay

• Patients who already have RNA expression testing demonstrating HER2 RNAexpression as well as IHC testing on the MDACC CLIA lab platform will beeligible for enrollment after review of results by the Precision OncologyDecision Support team without having to repeat HER2 IHC results as part ofpre-screening. Patients who have had HER2 2+ testing result performed outsideof MDACC will have to undergo MDACC HER2 IHC analysis before enrollment

• Women of childbearing potential must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry, for theduration of study participation, and for 7 months after completion of study drugadministration. Women should not breastfeed during the study treatment period andfor 7 months after completion of study drug administration. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Men treated orenrolled on this protocol must also agree to use adequate contraception prior tostudy entry, for the duration of study participation, and for 4 months aftercompletion of study drug administration. Female patients must not donate, orretrieve for their own use, ova from the time of screening throughout the studytreatment period and for at least 7 months after the final study drugadministration. Female patients may wish to consider preservation of ova prior toenrollment in the study. Male patients should refrain from freezing or donatingsperm 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 EXCLUSION CRITERIA:

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease. Patients with treated brain metastases are eligible iffollow-up brain imaging 4 weeks after central nervous system-directed therapy showsno evidence of progression

• Clinically significant cardiovascular condition including: (1) history of congestiveheart failure (New York Health Association class > 2), (2) any history of unstableangina, (3) myocardial infraction within the past 12 months, or (4) any history ofsupraventricular arrhythmia or ventricular arrhythmia requiring treatment orintervention

• History or presence of abnormal electrocardiogram (ECG) that, in the investigator'sopinion, is clinically meaningful

• Active or chronic corneal disorder including, but not limited to, Sjogren'ssyndrome, Fuchs corneal dystrophy (requiring treatment), history of cornealtransplantation, active herpetic keratitis, and/or active ocular conditionsrequiring ongoing treatment/monitoring such as wet age-related macular degenerationrequiring 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 orbiologic 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 aswarfarin. Low molecular weight heparin is permitted for prophylactic or therapeuticuse. 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 operatingpractice

• Pregnant women are excluded from the study because the study drugs areinvestigational or approved agents with the potential for teratogenic orabortifacient effects. Because there is an unknown but potential risk for AEs innursing infants secondary to treatment of the mother with any of the study drugs,breastfeeding should be discontinued if the mother is treated with any of the studydrug

• ADDITIONAL EXCLUSION CRITERIA FOR TREATMENT COHORTS:

• Patients must have adequate washout from prior therapy at the time of studytreatment initiation: 4 weeks from major surgery; 4 weeks from antibody-basedtherapy; 2 weeks or 5 half-lives (whichever is shorter) from any targeted therapy orsmall molecule therapy; 3 weeks or 5 half-lives (whichever is shorter) fromchemotherapy or 6 weeks in the case of certain therapies (e.g., extensiveradiotherapy, mitomycin C, and nitrosoureas); and 4 weeks from radiation therapy.Patients should have received no more than 3 prior lines of chemotherapy.Testosterone suppression as supportive treatment for castration-resistant prostatecancer and ovarian suppression in premenopausal patients with breast cancer thathave supportive treatment and not anticancer treatment role (with luteinizinghormone-releasing hormone analogs) will be allowed if the patients were on thesesupportive treatments before starting the study. Use of bone-modifying medications (bisphosphonates or denosumab) will be allowed. Palliative radiotherapy ofnon-target lesions is permitted, but presence of new or worsening metastases will beconsidered progressive disease. If there is clear evidence of clinical benefit,study treatment may be continued 2 weeks after completion of palliative radiotherapyto lesions that are non-target lesions. Patients can be on therapy during treatmentcohort screening

• Patients who are currently receiving any other investigational agent(s)

• Received systemic therapy with corticosteroids at > 20 mg/day prednisone orequivalent within 1 week prior to cycle 1 day 1

• Patients who have not recovered from AEs due to prior anticancer therapy (i.e., haveresidual toxicities > grade 1) with the exception of alopecia

• When the corrected QT interval (QTc) by Fridericia's formula is < 120 ms, > 450 msin males and > 470 ms in females. When the QTc by Rautaharju's formula is ≥ 120 ms, > 450 ms in males and > 470 ms in females

• Uncontrolled infection requiring intravenous antibiotic, antiviral, or antifungaluse

• Received a live, attenuated vaccine within 30 days prior to cycle 1 day 1. Enrolledpatients should not receive live vaccine during the study. Non-live COVID vaccineswill be allowed on study, but it is recommended to avoid their use during the firsttreatment cycle (from 3 days prior to cycle 1 day 1 through cycle 2 day 3)

• Patients with uncontrolled intercurrent illness including, but not limited to,ongoing or active infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, or psychiatric illness/social situations that wouldlimit compliance with study requirements

• Other concurrent medical or psychiatric conditions that, in the investigator'sopinion, may be likely to confound study interpretation or prevent completion ofstudy procedures and follow-up examinations

• COHORT A EXCLUSION CRITERIA:

• Patients with histologically documented advanced colorectal cancer, urothelialcancer, head and neck cancer, triple negative breast cancer (TNBC), HR-positivebreast cancer, HER2-positive breast cancer, small cell lung cancer, NSCLC, andendometrial cancer

• Patients who have received growth factor support within 2 weeks of study treatmentinitiation

• Coadministration of sacituzumab govitecan (IMMU-132) with inhibitors of UGT1A1 mayincrease systemic exposure to the active metabolite, SN-38. UGT1A1 inhibitors shouldnot be administered concomitantly with sacituzumab govitecan (IMMU-132) unless thereare no therapeutic alternatives

• Prior topoisomerase 1 inhibitor treatment

• Prior treatment with a Trop-2-targeting ADC

• Has active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease)or gastrointestinal (GI) perforation within 6 months of treatment cohort Aregistration

• COHORT B EXCLUSION CRITERIA:

• Patients with histologically documented advanced urothelial cancer, head and neckcancer, breast cancer, lung cancer, gastric cancer, gastroesophageal junctioncancer, esophageal cancer, prostate cancer, or penile cancer

• Concomitant use of strong inhibitors or strong inducers of cytochrome P450 (CYP)3A4.Washout period is 2 weeks prior to study treatment initiation

• History of uncontrolled diabetes mellitus within 3 months before the first dose ofstudy treatment. Uncontrolled diabetes mellitus is defined as hemoglobin A1c ≥ 8% orhemoglobin A1c between 7 and < 8% with associated diabetes symptoms (polyuria orpolydipsia) that are not otherwise explained

• Known active keratitis or corneal ulcerations. Patients with superficial punctatekeratitis are allowed if the disorder is being adequately treated

• Known hypersensitivity to enfortumab vedotin or to any excipient in the drugformulation of enfortumab vedotin (including histidine, trehalose dihydrate, andpolysorbate 20), or known hypersensitivity to biopharmaceutical produced in Chinesehamster ovary cells

• Prior treatment with an ADC with vedotin payload

• COHORT C EXCLUSION CRITERIA:

• Patients with histologically documented advanced breast cancer, non-small cell lungcancer (NSCLC), colorectal carcinoma (CRC), gastric cancer, or gastroesophagealjunction (GEJ) cancer

• Previous treatment with topoisomerase I inhibitors as a free form or as otherformulations, and ADCs with topoisomerase I inhibitor payloads

• Patients receiving treatment with chloroquine or hydroxychloroquine are not allowedto participate in the study, unless there is a washout period of at least 14 daysprior to the first dose of study drug

• History of non-infectious pneumonitis/interstitial lung disease (ILD), current ILD,or where suspected ILD that cannot be ruled out by imaging at screening

• Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3months of initiation of study drug, severe asthma, severe chronic obstructivepulmonary disease, restrictive lung disease, pleural effusion etc.)

• Any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoidarthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion ofpulmonary involvement at the time of screening

• Prior pneumonectomy

• History of severe hypersensitivity reactions to other monoclonal antibodies