Dose Escalation Study of Pazopanib Plus TH-302

NCT01485042 | Completed Phase 1 DMC

• 1 other identifier: Pro00031123
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

3 STUDY RATIONALE Based upon the above rationale, the investigators propose a phase I study combining Pazopanib with TH-302 in advanced solid tumors. Pazopanib is FDA approved at a dose of 800mg per day. Using this dose ensures consistency with standard clinical use. It also ensures using the dose most likely to induce maximal hypoxia, which in turn will help ensure maximal local activation of TH-302 (a hypoxia activated prodrug). TH-302 can be given as monotherapy at a weekly dose of 575 mg/m2. When TH-302 is combined with full doses of various chemotherapeutics, the recommended dose of TH-302 has ranged from 240 to 480 mg/m2. Little overlapping toxicity between TH-302 and pazopanib is expected. However to ensure patient safety, the starting dose for the combination will be conservative and use the TH-302 dose found safe with the majority of cytotoxic agents, 340 mg/m2 given days 1,8, 15 on an every 28 day cycle. Using a standard 3+3 design, the investigators will add increasing doses of TH-302 (340 mg/m2, 480 mg/m2, 575 mg/m2 given weekly, 3 weeks on/1 week off (the standard TH-302 dosing schedule) to the full monotherapy dose of pazopanib (800 mg p.o daily) with expected accrual ranging from 12-18 subjects. Once the recommended phase II dose is identified, the investigators will then enroll an expanded cohort of approximately 12-18 (i.e. total of 30 subjects overall) patients to better define the tolerability of this study drug combination. 4 STUDY OBJECTIVES 4.1 Primary

• To define the maximal tolerated dose (if any) and the recommended phase II doses for the combination of pazopanib plus TH-302 in patients with advanced solid tumors 4.2 Secondary
• To describe any dose limiting and non dose-limiting toxicities of this drug combination

Conditions

Solid Tumors

Keywords

Phase 1; pazopanib; TH-302; advanced solid tumors

Outcome Measures

Primary Outcomes (1)

• Maximal tolerated dose

  To define the maximal tolerated dose (if any) and the recommended phase II doses for the combination of pazopanib plus TH-302 in patients with advanced solid tumors

  12-18 months

Secondary Outcomes (1)

• Dose limiting or non dose limiting toxicities

  12-18 months

Study Arms (1)

Dose Escalation

EXPERIMENTAL

This is a Phase 1 dose escalation with an expanded cohort that will enroll at MTD.

Drug: Pazopanib and TH-302

Interventions

Pazopanib and TH-302 DRUG

Pazopanib 800 mg daily TH-302 IV on Days 1, 8, 15 at MTD Subjects will receive this regimen until disease progression.

Dose Escalation

Eligibility Criteria

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

You may qualify if:

• Histologically and/or cytologically confirmed malignant solid tumor that is refractory to standard therapies, or for which no standard therapies exist, or for whom pazopanib would be considered a therapeutic option.
• Disease must be measurable by RECIST 1.1 criteria (see Appendix 1).
• Age ≥ 18 years
• Karnofsky Performance status ≥ 80% (see Appendix 2)
• Life expectancy of at least 3 months
• Adequate bone marrow function as shown by:
• ANC ≥ 1.5 x 109
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 9 g/dL; Erythropoietin and transfusion support is permitted provided treatments are not required more than every 8 weeks. Hemoglobin must be stable above or equal to 9 g/dL for at least 2 weeks prior to day 1of study drug without blood transfusion to maintain hemoglobin level.
• Adequate liver function as shown by:
• serum bilirubin ≤ 1.5x ULN
• PT/PTT/INR ≤ 1.5x ULN
• ALT and AST ≤ 2.5x ULN
• Adequate renal function: creatinine clearance (estimated) ≥ 50 cc/min by Cockroft-Gault or 24 hour urine (see Appendix 6).
• Baseline MUGA or ECHO must demonstrate LVEF ≥ 50%

You may not qualify if:

• Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks from day 1 of study drug (including investigational agents, chemotherapy, radiation therapy, antibody based therapy, etc.)
• Patients who:
• have had a major surgery or significant traumatic injury within 4 weeks from day 1 of study drug,
• have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or
• are anticipated to require major surgery during the course of the study.
• Patients who have exhibited hypersensitivity reactions to pazopanib and/or a structural compound, biological agent, or formulation.
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent with the following exceptions:
• Intermittent steroids (not to exceed 4 mg every day) may be used on an as-needed basis
• Patients on physiologic replacement doses of steroids due to adrenal insufficiency for any reason may remain on these medications.
• Topical, inhaled or intra-articular corticosteroids
• Active brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. Treated, asymptomatic metastases are permitted provided the patient has been off steroids for at least 1 month prior to day 1 of study drug.
• Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or O2 saturation \<90% by pulse oximetry after a 2 minute walk or in the opinion of the investigator any physiological state likely to cause systemic or regional hypoxemia.
• Presence of poorly controlled atrial fibrillation (ventricular heart rate \>100 bpm)
• Previous history of CVA, TIA, angina pectoris, acute MI or history of recent re-perfusion procedures (e.g. PTCA), pulmonary embolus or untreated deep vein thrombosis (DVT) within 6 months from day 1 of study drug.
• NOTE: Subjects with recent DVT who have been therapeutically anti-coagulated for at least 6 weeks are eligible.

Sponsors & Collaborators

• Herbert Hurwitz, MD: lead
• National Comprehensive Cancer Network: collaborator
• GlaxoSmithKline: collaborator
• Threshold Pharmaceuticals: collaborator

Study Sites (1)

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Interventions

pazopanib; TH 302

Study Officials

• Herbert I Hurwitz, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: November 30, 2011
• First Posted: December 5, 2011
• Study Start: December 1, 2011
• Primary Completion: February 1, 2013
• Study Completion: March 1, 2014
• Last Updated: September 1, 2017

Record last verified: 2017-08

Locations

US (1)