PU-H71 in Patients With Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma That Have Not Responded to Standard Treatment

Study Overview
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Brief Summary
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Background: - PU-H71 is an experimental drug used to treat cancer. It works by blocking a protein in tumors. When this protein is blocked, it affects other proteins inside the cell that cancers need to grow. Researchers want to study whether PU-H71 is a safe and effective way to treat solid tumors and non-Hodgkin's lymphoma. Objectives: - To evaluate the safety and effectiveness of PU-H71 in solid tumors and non-Hodgkin's lymphoma that have not responded to standard treatments. Eligibility: - Individuals at least 18 years of age who have solid tumors or non-Hodgkin's lymphoma that have not responded to standard treatments. Design: Patients will be screened with a physical exam, medical history, blood tests, and imaging studies. Patients will receive PU-H71 as a 1-hour dose on days 1 and 8 of a 21-day cycle of treatment. The first treatment cycle will be done in the hospital so that patients can be monitored. The next treatment cycles will be done on an outpatient basis. Patients will have blood and urine tests and eye exams. Patients will provide tumor samples for study. Patients will have imaging studies to monitor tumor response to treatment. Patients will continue to take PU-H71 for as long as side effects remain tolerable and their tumor or lymphoma does not worsen. Study researchers may adjust the dose if needed.

Detailed Description
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Background: -PU-H71 is a synthetic HSP90 inhibitor which can bind both open and closed conformations of HSP90. It demonstrates extended tumor retention and client protein degradation, while being rapidly cleared from normal tissues. It has shown complete tumor responses and retained sensitivity to retreatment in vivo. Primary Objectives: To establish the safety and tolerability of PU-H71 administered on a once weekly, 2 weeks out of 3 schedule, in patients with refractory solid tumors and lowgrade non-Hodgkin's lymphoma (NHL). To establish the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PU-H71 administered on a once weekly, 2 weeks out of 3 schedule, in patients with refractory solid tumors and low-grade NHL. To determine the pharmacokinetics of PU-H71 administered on a once weekly, 2 weeks out of 3 schedule, in patients with refractory solid tumors and low-grade NHL. Secondary Objectives: To perform pharmacodynamic studies to ascertain PU-H71 effect on HSP70 in tumor tissue, serum, and peripheral blood mononuclear cells (PBMCs) at the MTD. To perform pharmacodynamic studies to ascertain PU-H71 effect on HSP90 client proteins in tumor tissue at the MTD. Eligibility: -Study participants must have histologically confirmed solid tumor malignancy or low-grade non-Hodgkin s lymphoma that has progressed or recurred after at least one line of chemotherapy or for which no standard treatment option exists; no therapy within 4 weeks prior to entering the study; age greater than or equal to 18 years; Eastern Cooperative Oncology Group (ECOG) less than or equal to 2; life expectancy > 3 months; and adequate organ and marrow function. Patients entering on the expansion cohort at the MTD must have disease amenable to biopsy with willingness to undergo pre- and post-treatment biopsies. Study Design: This study will follow a modified accelerated titration design (Simon et al., 1997). The accelerated phase ends when 1 patient experiences a dose-limiting toxicity or 2 patients experience Grade 2 drug-related toxicity during the first cycle; after which the study will follow the standard 3 + 3 design. PU-H71 will be administered intravenously over one hour, once weekly, 2 weeks out of 3, (i.e., on days 1 and 8) every 21 days. Pharmacokinetics (PK) and pharmacodynamics (PD) studies will be conducted during cycle 1. Up to 10 additional patients will be entered at the MTD to further define toxicity and perform PD studies at this dose; pre- and post-treatment tumor biopsies will be mandatory for these patients. Computed tomography (CT) scans will be performed at baseline and every 2 cycles (6 weeks) for restaging. Up to 100 patients may be treated.

Official Title
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Phase I Study of the Hsp90 Inhibitor, PU-H71, in Patients With Refractory Solid Tumors and Low-Grade Non-Hodgkin's Lymphoma

Conditions
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Solid Tumors, Lymphoma

Intervention / Treatment
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* Drug: PU-H71


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histologically documented (confirmed at the Laboratory of Pathology, National Cancer Institute (NCI)) solid tumor malignancy or low-grade non-Hodgkin's lymphoma that is metastatic or unresectable, for which standard curative measures do not exist, or whose disease has progressed or recurred following at least one line of standard therapy. Patients must have measurable or evaluable disease. Patients must have completed any chemotherapy, radiation therapy, or biologic therapy greater than or equal to 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a Phase 0 study (also referred to as a pre-Phase I study where a sub-therapeutic dose of drug is administered). Patients must have recovered to eligibility levels from prior toxicity or adverse events. Patients receiving bisphosphonates for any cancer are eligible to participate. Age greater than or equal to 18 years. An Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Life expectancy > 3 months. Patients must have normal or adequate organ and marrow function as defined below: Absolute neutrophil count greater than or equal to 1,500/microL Platelets greater than or equal to 100,000/microL Total bilirubin less than or equal to 1.5 times institutional upper limit of normal (ULN) Aspartate aminotransferase (AST)serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(SGPT) less than or equal to 2.5 times institutional ULN Creatinine <1.5 times ULN; OR Measured creatinine greater than or equal to 60 mL/minute for patients with clearance creatinine levels greater than or equal to 1.5 times ULN The effects of PU-H71 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry, for the duration of study participation, and for 2 months after completion of study. Women of childbearing potential must have a negative pregnancy test within 72 hours of enrollment in order to be eligible. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, the treating physician should be notified immediately. Because there is an unknown but potential risk to nursing infants secondary to treatment of the mother with PU-H71, breastfeeding should be discontinued if the mother is treated with PU-H71. During the expansion phase of the protocol, patients must have: Disease amenable to biopsy Willingness to undergo pre- and post-treatment tumor biopsies Ability to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 3 months after treatment of the brain metastases. Patients with clinically significant intercurrent illnesses, including but not limited to, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Corrected QT interval (QTc) > 450 msec for men and > 470 msec for women. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetics (PK) interactions with PU-H71. Pregnant women are ineligible because the effects of PU-H71 on the developing human fetus are unknown. Breastfeeding should be discontinued if the mother is treated with PU-H71 since there is an unknown but potential risk for adverse events in nursing infants.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PU-H71<br>PU-H71 will be administered intravenous (IV) over one hour, once weekly, 2 weeks out of 3, (i.e., on days 1 and 8) every 21 days | Drug: PU-H71<br>* PU-H71 is a synthetic HSP90 inhibitor which can bind both open and closed conformations of HSP90. It demonstrates extended tumor retention and client protein degradation, while being rapidly cleared from normal tissues. It has shown complete tumor responses and retained sensitivity to retreatment in vivo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Cycle 1 Dose-limiting Toxicities (DLTs) | A DLT was defined as an adverse event that occurred during cycle 1, was thought to be related to study drug administration, and met one of the following criteria: grade ≥ 3 non-hematologic toxicities (except diarrhea, nausea, vomiting without maximal supportive therapy; alopecia), grade 4 hematologic toxicities (except lymphopenia), and grade 2 ocular toxicity that did not resolve to ≤ grade 1 within 2 weeks. Occurrence of a DLT resulted in a dose reduction following resolution to grade ≤ 2. No more than 2 dose reductions were allowed per patient on study. | Cycle 1 (21 days) | 
| Number of Participants With Adverse Events Possibly, Probably, or Definitely Related to Study Drug | Severity of adverse events were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 1 Mild adverse event (AE), Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, and Grade 5 Death related to AE. | 3 years and two months and 11 days | 
| Maximum Tolerated Dose (MTD) of PU-H71 | The MTD is the dose level at which no more than 1 of 6 patients experience DLT during the first cycle of treatment, and the dose below that at which at least 2 (of ≤ 6) patients have DLT as a result of the drug. | Cycle 1 (21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) | Number of Participants According to Best Response Per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by computed tomography (CT): Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions. | Baseline and every 6 weeks up to 18 weeks | 
| Number of Days on Treatment |  | up to 126 days | 
| Maximum Observed Plasma Concentration (Cmax) | The maximum concentration (Cmax) was determined by visual inspection of the concentration versus time data. | Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1. | 
| Terminal Half-life (T1/2) | The terminal half-life (t1/2) was derived from the plasma concentration vs. time data. | Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1. | 
| Area Under the Concentration-Time Curve From Time 0 to 24 Hours [AUC(0-24)] | Area Under the Concentration-Time Curve From Time 0 to 24 Hours was estimated by trapezoidal rule calculations | Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1. | 
| Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] | Area Under the Concentration-Time Curve From Time 0 to Infinity was estimated by trapezoidal rule calculations | Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1. | 
| Urinary Excretion (%) | Elimination of the drug was investigated by analysis of an aliquot of the total urine collected in 24 h. | Every void post-treatment on day 1 of cycle 1 | 
| Clearance | Clearance was calculated from drug dose and AUC(0-∞). | Before the start of infusion, 30 minutes after the start of infusion, 5 minutes before completion of infusion, and at 1.5, 2, 3, 4, 7, 10, and 24 hours after the start of infusion on day 1 during cycle 1. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Targeted Therapy, Solid Tumors, Lymphoma, Non-Hodgkin Lymphoma, Solid Tumor