Phase I Trial of PX-478

Study Overview
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Brief Summary
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This study is being conducted to determine the safety and biologic activity of PX-478, and to allow for observation of any preliminary evidence of antitumor activity in patients with advanced metastatic cancer.

Official Title
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A Phase 1 Trial of Oral PX-478 (a HIF-1α Inhibitor) in Patients With Advanced Solid Tumors or Lymphoma

Conditions
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Advanced Solid Tumors, Lymphoma

Intervention / Treatment
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* Drug: PX-478


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has signed the informed consent and must be considered legally capable of providing his or her own consent for participation in this study. The patient has a histologically or cytologically confirmed diagnosis of advanced solid tumor or lymphoma and has failed or is intolerant of standard therapy. The patient is ≥18 years of age. ECOG performance status 0 to 1. The patient has a predicted life expectancy of at least 12 weeks. Patients must have discontinued prior chemotherapy or other investigational agents for at least three weeks prior to receiving the first dose of study drug (six weeks for mitomycin C, nitrosureas, vaccines, or antibody therapy) and recovered from the toxic effects of that treatment (recovered to baseline or ≤Common Toxicity Criteria for Adverse Events (CTCAE) grade 1). Patients must have discontinued any radiation therapy at least four weeks prior to entry into the study and have recovered from all radiation-related toxicities (recovered to baseline or ≤CTCAE grade 1). The patient has adequate hematologic function defined as: WBC count >3,000 cells/μL; platelets >100,000/μL; hemoglobin >9 g/dL (may be transfused to this level); ANC >1500 cells/μL. The patient has adequate hepatic function defined as: bilirubin <1.5 mg/dL; aspartate aminotransaminase (AST/SGOT) & alanine aminotransferase (ALT/SGPT) <2.5 x ULN or <5 x ULN if due to metastatic disease. The patient has adequate renal function as defined by serum creatinine level <1.5 mg/dL. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method; abstinence) prior to study entry and for the duration of study participation. The patient, if a man, agrees to use effective contraception or abstinence. Exclusion Criteria: Patients with any active infection requiring i.v. antibiotics at study entry. Any serious concomitant systemic disorders that in the opinion of the investigator would place the patient at excessive or unacceptable risk of toxicity. Surgery within the four weeks prior to the first dose of PX 478. Significant central nervous system (CNS) or psychiatric disorder(s) that preclude the ability of the patient to provide informed consent. Known or suspected brain metastases that have not received adequate therapy. In the case of previously treated brain metastases, a minimum of four weeks interval between completion of radiation therapy and registration on study with radiologic evidence of stable or responding brain metastases is required. In the setting of previous CNS metastasectomy, adequate (minimum four week) recovery from surgery and/or radiation therapy should be documented. Patients with a history of seizures, non-healing wounds, or arterial thrombosis. Patients with unstable atrial or ventricular arrhythmias requiring control by medication; any cardiac ischemic event experienced within the preceding six months; prior history of congestive heart failure requiring therapy. Patients who are breastfeeding or pregnant (confirmed by serum β-HCG within 10 days prior to the start of study treatment if applicable). Patients with total gastrectomy or partial bowel obstruction. Any condition that could jeopardize the safety of the patient and compliance with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Drug<br>Dose Escalation | Drug: PX-478<br>* Oral formulation, dose escalation, taken on days 1 to 5 of a 21 day cycle until progression or development of unacceptable toxicity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the MTD of PX-478 administered orally on days one to five of a 21 day cycle |  | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety profile of PX-478 when administered orally on days one to five of a 21 day cycle |  | 42 days | 
| To evaluate pharmacodynamic measures of the effects of PX 478 on the HIF 1-alpha pathway, and related tumor markers |  | 42 days | 
| To determine the PK profile of PX 478 when administered orally on days one to five of a 21 day cycle |  | 21 days | 
| To evaluate the effects of PX 478 on tumor blood flow and vascular permeability as measured by DCE MRI |  | 21 days | 
| To evaluate the anti-tumor activity of PX 478 in patients with advanced malignancies |  | 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, advanced cancer, lymphoma