A Trial to Evaluate Safety, Tolerability, and Preliminary Efficacy of Misetionamide (GP-2250) as Monotherapy or in Combination With Gemcitabine

Official title

A Phase 1 Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Misetionamide (GP-2250) as Monotherapy or in Combination With Gemcitabine in Subjects With Advanced Solid Tumors

Overview

This is a phase 1 dose escalation trial of monotherapy misetionamide (also known as GP-2250) currently enrolling patients with platinum-resistant ovarian cancer (PROC) into Part 2 of the study. Part 1 of the study evaluating misetionamide in combination with gemcitabine in subjects with advanced pancreatic cancer previously treated with 5-fluorouracil-based chemotherapy completed enrolment.

Detailed description

Part 2 of the trial will use a 3+3 dose escalation design. Subjects will continue to receive treatment until disease progression assessed by RECIST V1.1 criteria, clinical disease progression as assessed by the Investigator, unacceptable toxicity, subject request for withdrawal or lost to follow-up, Investigator assessment that risk outweighs benefit or study closure by the Sponsor. Part 2 will study PROC patients with disease progression within 6 months of the last dose of platinum-based chemotherapy and maximum of 2 prior regimens with at least one regimen causing the patient to meet the definition of platinum resistance.

Interventions

• Drug misetionamide (also known as GP-2250)
  Part 2: misetionamide monotherapy for pharmacokinetics, safety, and tolerability.

Primary outcome measures

• Safety, tolerance and recommended misetionamide dose for subsequent studies in PROC

Secondary outcome measures (1)

• Evaluation of preliminary anti-tumor efficacy

Eligibility criteria

Abridged Inclusion Criteria:

• Capable of giving signed informed consent: Regulatory, Ethical, and Trial Oversight Considerations which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Subjects age > 18 years at the time of trial entry.
• Pathologically proven platinum-resistant epithelial ovarian, fallopian, or primary peritoneal cancer, with high-grade serous ovarian carcinoma (HGSOC) or a predominantly serous/endometroid component. Platinum-resistant disease, defined as disease progression within 6 months of last dose of platinum-based chemotherapy.
• Maximum of 2 prior regimens for platinum-resistant disease. Subjects who are positive for high FR alpha (defined per the FDA approved companion diagnostic test (ELAHERE prescribing information) must have received MIRV. Candidates for MIRV with contraindications or documented intolerance are eligible pending documentation of discussion with the Medical Monitor.
• CT/MRI evidence of measurable disease per RECIST Version 1.1 defined as at least one lesion not previously irradiated that can be measured at baseline as 10 mm in the longest diameter (except lymph nodes which must have a short axis of 15 mm). Tumor lesions in previously irradiated area or in area subject to other loco-regional therapy are usually not considered measurable unless progression has been demonstrated in the lesion. Lesions selected as targets for response assessment should not be biopsied.
• ECOG performance status of 0-1
• Subjects with known central nervous system metastasis must have undergone brain targeted treatment and must be asymptomatic or radiographically and clinically stable (including not requiring steroids or anti-seizure medications) for at least 4 weeks prior to enrollment.
• Subjects must have adequate organ function as indicated by the following laboratory values:

• Absolute neutrophil count (ANC) ≥ 1,500 /mL
• Platelets ≥ 100,000 / mL
• Hemoglobin ≥ 9 g/dL
• Serum creatinine ≤ 1.5 X upper limit of normal (ULN)
• Serum total bilirubin ≤ 1.5 × ULN
• Aspartate aminotransferase (AST), (Serum glutamic oxaloacetic transaminase \[SGOT\]), alanine aminotransferase (ALT), and (Serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 × ULN OR ≤ 5 × ULN for subjects with liver metastasis
• International Normalized Ratio (INR) and/or Prothrombin Time (PT) ≤ 1.5 × ULN
• Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN
• Serum Albumin ≥ 3 g/dL measured at two time points: no less than 2 weeks before the 1st dose of misetionamide and within one week prior to the 1st dose. Subjects showing a decrease of > 20% at the 2nd measurement are excluded.
• Limited concomitant radiotherapy for pain control is allowed in the 5 weeks prior to initial dose.
• Women of childbearing potential (WOCBP) must have a negative urine pregnancy test.
• Subjects must use adequate contraception for the duration of the trial and for at least 3 months after the last dose and refrain from tissue donation during this period. .
• All acute toxic effects of any prior anti-tumor therapy resolved to Grade < 1or baseline before start of dosing (exceptions are alopecia and Grade 2 peripheral neuropathy).

Abridged Exclusion Criteria:

• Diagnosis of any active malignancy other than platinum-resistant ovarian cancer within the past 2 years (not including non-melanoma skin carcinoma, ductal carcinoma in situ of the breast, or carcinoma in situ of uterine cervix treated with curative intent).
• Subjects has a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonia or multiple allergies, clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome within < 6 months prior to the start of study treatment, symptomatic or uncontrolled arrhythmia, congestive heart failure, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or ascites requiring paracentesis in the 4 weeks prior to Screening.
• Primary refractory disease (defined as failure to achieve at least a partial response (PR) to their initial platinum-based chemotherapy).
• Radiotherapy (RT) to target lesions, chemotherapy, or other systemic anti-cancer therapy, including prior anti-angiogenic treatment (e.g. bevacizumab) within 4 weeks prior to starting treatment.
• Ascites including history of therapeutic paracentesis within the 2 weeks prior to signing informed consent.
• Any other medical, psychiatric, or social condition deemed by the Investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate and participate in the trial, or which would interfere with the interpretation of the results.
• Subject has undergone major surgery, other than diagnostic surgery within 4 weeks prior to Day 1 of treatment in this study.
• Prior history or current signs of hyphema or glaucoma.
• History of sickle cell disease or hereditary non-spherocytic hemolytic anemia.
• Baseline QTc interval >480 msec for female subjects or >450 msec for male subjects.
• Subject is unwilling or unable to comply with study procedures or planning to take a vacation for >7 consecutive days during the course of the study.
• First degree relative of the investigator, study staff or the sponsor.
• Any chemotherapy administered within 3 weeks or 5 half-lives (whichever is shorter) before first dose of misetionamide; other anti-cancer therapy (including surgery, radiotherapy, immunotherapy, hormone therapy, or targeted therapy) administered within 4 weeks or 5 half-lives (whichever is shorter) before the first dose of misetionamide; or within 6 weeks in the case of certain therapies (mitomycin C and nitrosoureas).
• Investigational therapy administered within 4 weeks or 5-half lives (whichever is shorter) before the first dose of misetionamide.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• Rush University Medical Center — Chicago
• University of Kansas Cancer Center — Fairway
• Beth Israel Deaconess Medical Center — Boston
• Abramson Cancer Center at the University of Pennsylvania — Phildelphia

Publications

• Buchholz M, Majchrzak-Stiller B, Hahn S, Vangala D, Pfirrmann RW, Uhl W, Braumann C, Chromik AM. Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo. BMC Cancer. 2017 Mar 24;17(1):216. doi: 10.1186/s12885-017-3204-x. PMID 28340556
• Majchrzak-Stiller B, Buchholz M, Peters I, Waschestjuk D, Strotmann J, Hohn P, Hahn S, Braumann C, Uhl W, Muller T, Mohler H. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J Cell Mol Med. 2023 Jul;27(14):2082-2092. doi: 10.1111/jcmm.17825. Epub 2023 Jun 30. PMID 37390227
• Kim MS, Glassman D, Handley KF, Lankenau Ahumada A, Jennings NB, Bayraktar E, Foster K, Joseph R, Lee S, Coleman RL, Sood AK. Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer. Cancer Med. 2024 Aug;13(15):e70031. doi: 10.1002/cam4.70031. PMID 39114948

Identifiers

NCT: NCT03854110 · GP-2250-1001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗