A Phase 2 Study to Evaluate the Triplet Combination of Pemetrexed Plus AB928 (Etrumadenant) + AB122 (Zimberelimab) in Patients With Previously Treated Advanced or Metastatic MTAP Deficient Urothelial Carcinoma

NCT05335941 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2021-0774NCI-2022-02708
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 2 open-label, single-arm trial for patients with MTAP-deficient advanced urothelial cancer who had received prior immunotherapy. This is a single site study at the University of Texas MD Anderson Cancer Center. This study will allow patients in second line of treatment for advanced urothelial ca or beyond. All patients must have been previously treated with immune checkpoint inhibitor (ICI) therapy as per current standard of care.

Conditions

Urothelial Carcinoma; Metastatic Cancer

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0 and Number of Participants With Complete or Partial Response as their Best Overall Response per RECIST v1.1.

  through study completion, an average of 1 year

Study Arms (1)

Pemetrexed Plus AB928 (Etrumadenant) Plus AB122 (Zimberelimab)

EXPERIMENTAL

All patients will receive combination therapy of pemetrexed and ZIMBERELIMAB (AB122) intravenously every 3 weeks as well as ETRUMADENANT (AB928) orally daily.

Drug: Pemetrexed; Drug: Zimberelimab; Drug: Etrumadenant

Interventions

Pemetrexed DRUG

Given by vein (IV)

Also known as: LY23151, Alimta®, MTA, Multitargeted Antifolate, NSC-698037

Pemetrexed Plus AB928 (Etrumadenant) Plus AB122 (Zimberelimab)

Zimberelimab DRUG

Given by vein (IV)

Also known as: AB122

Pemetrexed Plus AB928 (Etrumadenant) Plus AB122 (Zimberelimab)

Etrumadenant DRUG

Given by PO

Also known as: AB928, Etruma

Pemetrexed Plus AB928 (Etrumadenant) Plus AB122 (Zimberelimab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years of age at time of screening
• Patients must have histologic confirmation of MTAP-deficient metastatic urothelial carcinoma. MTAP-deficiency must be verified by institutional CLIA-certified IHC or by Next gen sequencing (such as FoundationOne or MDACC genomic analysis) showing copy number loss of MTAP gene. Histological variants such as glandular, squamous, sarcomatoid, micropapillary, plasmacytoid, and small cell changes will be allowed for this trial if these tumors are MTAP-deficient.
• Patients can be considered for second line of therapy or beyond (after ICI with PD-(L)1 agent). Any prior intravesical therapy is allowed and does not count as a prior line of therapy.
• All patients must have measurable disease by RECIST v1.1 and tumors of sufficient sizes for biopsy. In general, liver and lung lesions should be at least 1.0 cm, and patients with lymph node-only disease should have lesions of ≥ 1.5 cm in shortest dimension.
• Patients with disease confined to bone may be eligible if a measurable lytic defect is present. The study PI is the final arbiter in questions related to measurability. Patients with a three-dimensional mass or pelvic sidewall fixation on bladder examination under anesthesia are considered to have measurable disease.
• Patients must have an ECOG performance status ≤ 2.
• Adequate liver function as defined by AST or ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if documented liver metastases are present.
• Total bilirubin ≤ 1.5 x ULN, except subjects with Gilbert's syndrome or liver metastases, who must have a baseline total bilirubin ≤ 3.0 mg/dL.
• Adequate bone marrow reserves as define by an ANC ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL (may have been transfused), and platelets ≥ 100 x 109/L.
• Adequate renal function as defined by a normal serum creatinine, or a creatinine clearance ≥ 45 ml/min \[either measured using a 24 hour urine, calculated using CockroftGault, or estimated using the MDRD method from the National Kidney Disease Education Program (NKDEP) (the method reported by MDACC laboratories)\] Cockroft-Gault formula: CrCl = \[(140-age) • wt(kg)\]/\[72 •Creat (mg/dL)\] (Multiply by 0.85 for females)
• Negative serum or urine pregnancy test at screening for women of child-bearing potential.
• Female participants of reproductive potential, defined as not surgically sterilized and between menarche and 1 year post menopause, must have a negative serum pregnancy test within 4 weeks prior to initiation of study treatment
• Female participants of reproductive potential and male participants with female partners of reproductive potential must remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive measures from the start of study treatment until 30 days after the last dose of etrumadenant, 90 days after the last dose of zimberelimab, 180 days after the last dose of pemetrexed, whichever is longer.
• Please refer to appendix 5
• The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.

You may not qualify if:

• QTc ≥480 msec using Fredericia's QT correction formula
• Due to the potential risk for drug-drug interactions with etrumadenant, participants must not have had:
• a. Treatment with known BCRP substrates with a narrow therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of and throughout study treatment b. Treatment with known P-gp substrates with a narrow therapeutic window, administered orally (e.g., digoxin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment c. Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment d. Refer to the following for more examples of relevant substrates, inhibitors, and inducers with the potential for drug-drug interactions with etrumadenant: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers
• c. Any gastrointestinal condition that would preclude the use of oral medications (e.g., difficulty swallowing, nausea, vomiting, or malabsorption)
• d. Prior treatment with an agent targeting the adenosine pathway
• e. History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins
• f. Primary central nervous system (CNS) malignancies or CNS metastases, including leptomeningeal metastases, are not allowed. Subjects with previously treated brain metastases will be allowed if the brain metastases have been stable for at least 4 weeks following prior treatment and no ongoing steroid requirement.
• g. Any other malignancy from which the patient has been disease-free for less than 2 years, except for non-melanomatous skin cancer, controlled localized prostate cancer, controlled thyroid papillary carcinoma, and in situ carcinoma of any site.
• h. Women who are pregnant or breastfeeding or intend to become pregnant during their participation in the study.
• i. Presence of large third space fluid which cannot be controlled by drainage. For patients who develop or have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before or during initiation of Pemetrexed therapy, consideration should be given to draining the effusion prior to dosing. However, if, in the investigator's opinion, the effusion represents progression of disease, the patient should be discontinued from study therapy.
• j. Patients with active inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], Systemic Lupus Erythematosus or autoimmune vasculitis \[e.g., Wegener's Granulomatosis\] are excluded from this study.
• k. Any condition requiring systemic treatment with corticosteroids (\>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids, steroids as premeds for hypersensitivity reactions, and adrenal replacement steroids doses ≤10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• l. History of primary immunodeficiency.
• m. Patients who have prior organ transplantation, including allogeneic stem-cell transplant.
• o. True positive test results for active hepatitis A, B, or C during screening.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Neoplasm Metastasis

Interventions

Pemetrexed; zimberelimab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• Omar Alhalabi, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2022
• First Posted: April 20, 2022
• Study Start: June 13, 2023
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: March 4, 2026

Record last verified: 2026-02

Locations

US (1)