Phase I safety and pharmacokinetic test of intravenous gamitrinib for advanced solid tumors and lymphoma

PH-139: A Phase I Safety and Pharmacokinetic Study of Gamitrinib Administered Intravenously to Patients With Advanced Cancer

This will test whether weekly IV gamitrinib is safe and how it is processed in people with advanced solid tumors or lymphoma.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 42 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fox Chase Cancer Center (Academic / other)
• Drugs / interventions: radiation, gamitrinib
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT04827810 on ClinicalTrials.gov

What this trial studies

This is a first-in-human, open-label phase I dose-escalation and dose-expansion program of gamitrinib, a mitochondrial-targeted Hsp90 inhibitor, given as a one-hour intravenous infusion once weekly for four weeks per 28-day cycle. The dose-escalation cohort (up to ~36 patients) will identify dose-limiting toxicities and the maximum tolerated dose, followed by expansion cohorts to refine the recommended phase II dose and schedule. Tumor response will be measured by RECIST v1.1 or RECIL 2017 criteria as appropriate, and the expansion cohort requires pre- and on-treatment tumor biopsies to study pharmacodynamics. Safety, tolerability, and pharmacokinetics are the primary focus given this is the first clinical experience with this agent.

Who should consider this trial

Good fit: Adults with histologically confirmed advanced solid tumors or lymphoma that are refractory to standard therapies, who have measurable disease and (for expansion cohorts) are willing to undergo required core biopsies, are the intended candidates.

Not a fit: Patients with curable disease, those unable to tolerate IV infusions or invasive biopsies, or those with poor organ function that precludes protocol treatments are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, gamitrinib could offer a new treatment option that targets mitochondrial Hsp90 to slow cancer growth in patients with advanced, treatment-refractory tumors.

How similar studies have performed: Preclinical studies showed anticancer activity and a distinct mechanism, but this is the first-in-human trial so clinical benefit in patients has not yet been demonstrated.

Eligibility criteria

Inclusion Criteria:

* Histologically confirmed diagnosis of advanced cancer refractory to standard of care therapy, or for whom no standard of care therapy is available. Any numbers of prior therapies are allowed.
* Dose escalation phase: Solid tumors and lymphoma may have measurable or evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1) or as per RECIL 2017 criteria
* Dose expansion phase:

  i. All patients must have at least one site of measurable disease as defined by RECIST v. 1.1. or RECIL 2017, for solid tumors and lymphoma, respectively ii. Patients in the expansion cohort must have at least one non-target lesion deemed safe to biopsy, in the opinion of the investigator, and be willing to undergo mandatory core biopsies. This includes pre-treatment and an on-treatment biopsy. Biopsies at the time of progression are highly desired, but optional.

iii. The lesion(s) which will be used for response assessment may not be biopsied iv. Target lesions that have been previously irradiated will not be considered measurable unless increase in size is observed following completion of radiation therapy

* All previous therapies of cancer, including radiotherapy major surgery and investigational therapies must be discontinued for ≥14 days (≥ 28 days for mitomycin C or nitrosoureas) before Cycle 1 Day 1 (C1D1), and all acute effects of any prior therapy must have resolved to baseline severity or Grade ≤ 1 Common Terminology Criteria for Adverse Events (CTCAE v5), except alopecia or parameters defined in this eligibility list.
* Age \> 18 years.
* ECOG performance status 0- 2
* Patients must have normal organ and marrow function as defined below
* Absolute neutrophil count ≥1,500/mm3 without growth factor use ≤ 7 days prior to C1D1 Platelets ≥85,000/mm3 without platelet transfusion ≤ 7 days prior to C1D1 Hemoglobin \>8.5 mg/dL without red blood cell transfusion ≤ 7 days prior to C1D1 Total serum bilirubin \<1.5 X upper limit of normal (ULN) (except for patients with documented Gilbert's syndrome) AST (SGOT)/ALT (SGPT) ≤2 X ULN; ≤ 5 X ULN if liver dysfunction is felt to be secondary to tumor burden Serum creatinine ≤ 1.5 X ULN (OR creatinine clearance ≥ 60 mL/min/1.73 m2) Serum or urine pregnancy test (WOCBP only) negative ≤7 days of C1D1
* Ability to understand and willingness to sign a written informed consent, HIPAA consent document and comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
* Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Male patients must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. The decision of effective contraception will be based on the judgment of the principal investigator or a designated associate.

Exclusion Criteria:

* Patients with symptomatic brain metastases are excluded. Patients with asymptomatic and treated CNS metastases may participate in this trial. The patient must have completed any prior treatment for CNS metastases \> 28 days prior to study entry, including radiotherapy or surgery. Concurrent use of steroids for the treatment of brain metastasis are not permitted.
* Current treatment on another (therapeutic) clinical trial
* Hypertension not adequately controlled with medications (\>150/100 mm Hg despite optimal medical therapy)
* Active bacterial fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), requiring treatment with IV antibiotic, IV anti-fungal, or anti-viral (Testing is not required for eligibility).
* Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness (testing is not required for eligibility).
* Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the patient inappropriate for entry into the study
* Pregnant or breast feeding. Refer to section 4.4 for further detail.

Where this trial is running

Philadelphia, Pennsylvania

• Fox Chase Cancer Center — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Study coordinator: Anthony Olszanski, MD

Conditions Lymphoma; Advanced Solid Tumor