Dose Escalation Study of Pazopanib Plus TH-302 — PATH  

Solid Tumors Clinical Trial

Official title: Phase I Dose Escalation of Pazopanib Plus TH-302 in Advanced Solid Tumors

Status Completed

Clinical Trial 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

Clinical Trial Description

STUDY DESIGN 5.1 Study Description This open-label, non-randomized phase I trial is designed to assess the safety, tolerability and maximum tolerated dose (MTD)/recommended phase II dose (RPTD) of TH-302 plus pazopanib in adult subjects with advanced solid tumors.

Patients will be accrued (enrolled) at Duke University Medical Center. Accrued (enrolled) subjects are defined as subjects who give informed consent. Approximately 50 subjects may be enrolled to ensure the trial obtains approximately 30 evaluable subjects.

Evaluable subjects are defined as those subjects who give informed consent, meet inclusion/exclusion screening criteria, received study drug treatment and completed the first cycle of safety assessments or have dose limiting toxicity that precludes completing the full cycle of assessments.

Please note that the number of accrued subjects exceeds the number of evaluable subjects for the following reasons:

1. Screen failures: Subjects with informed consent that do not meet inclusion/exclusion screening criteria.

2. Treated patients: Subjects with informed consent that meet the inclusion/exclusion criteria and received study drug treatment but did not complete the first cycle of safety assessments for primary study end points (e.g. those subjects who have disease progression or inter-current illness).

There will be two stages to this Phase I study. Stage 1 will be the dose escalation component to determine safety and the recommended phase II dose (RPTD) for TH-302 plus pazopanib combination. Dose escalation will begin with cohort 1 and continue as described in Table 5.1.

Stage 2 will be an expanded cohort which will better describe the tolerability and toxicity profile and (2) to further assess biomarkers related to mechanisms of the study agents. The treatment schedule will be as follows:

Table 5.1 Cohort Doses Cohort # subjects Threshold 302 mg/m2, intravenously Days 1, 8, 15 Pazopanib mg, orally daily

• 1 3-6 240 800 Starting Dose

1. 3-6 340 800

2. 3-6 480 800

3. 3-6 575 800 Expanded Cohort 12-18 RPTD 800

Subjects will be treated on 28 day cycles after satisfying eligibility and screening criteria.

Intermediate dosing levels may be explored. Toxicity will be assessed every visit and as clinically indicated. Efficacy will be assessed every 2 cycles and as clinically indicated.

Dose Escalation and Treatment Schema

The NCI Common Toxicity Criteria version 4.0 will be used to grade adverse events. The following adverse events will be considered dose limiting toxicity (DLT) if occurring during the first cycle of treatment and deemed to be related to study treatment:

• Hematologic toxicity: Any grade 4 neutropenia, thrombocytopenia or anemia or grade ≥ 3 neutropenia or thrombocytopenia lasting over 7 days

• Any grade 3 thrombocytopenia associated with bleeding

• Neutropenic fever

• Nausea,Vomiting or Diarrhea grade 3 and lasting 4 days despite adequate supportive measures

• Grade ≥ 3 ALT or AST elevation > 7 days

• Other non-hematologic toxicity grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable.

• Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity

• Any treatment-related death or treatment-related hospitalization

Management and dose modifications associated with adverse events are outlined in Sections 9 and 10.

Dose escalation will proceed in Stage 1 within each cohort according to the following scheme:

Number of Patients with DLT at a Given Dose Level Escalation Decision Rule 0 out of 3 Enter 3 subjects at the next dose level.

1 out of 3 Enter 3 more subjects at this dose level. < 1 out of 6 (a) Proceed to the next dose level OR (b) This will be the recommended MTD/RPTD if at highest dose level. > 2 out of 3-6 Dose escalation will be stopped. Three (3) additional subjects will be entered at the next lowest dose level (if only 3 subjects were treated at this level).

• 3 subjects with advanced solid tumors will be accrued at the starting dose level. If no DLTs are seen, 3 subjects will be enrolled in the next dose level.

• Subjects will be monitored for at least one full cycle before advancement to the next dose level.

• If one of three subjects has DLT at a given dose level, then an additional three subjects will be enrolled at that dose level.

• If 1/6 subjects experiences DLT at a given dose level, then escalation will continue to the next dose level.

• If ≥ 2 out of 3-6 subjects have DLT at any dose level, then that dose level will be considered to have unacceptable toxicity, and the next lower dose level will be expanded to 6 patients. In this case, the next lower dose level will be declared as the MTD provided ≤ 1/6 subjects have DLT (otherwise, dose will be further de-escalated). In cases where the only toxicity seen at this lower dose level is Grade ≤ 2, re-escalation for intermediate dosing will be considered. If there is uncertainty about study drug attribution to DLT then re-escalation to full doses is also permitted.

• If > 33% of subjects has DLT at any dose level, then that dose level will be considered to have unacceptable toxicity. The dose level immediately below the one with unacceptable toxicity will be the recommended phase II dose.

• If no unacceptable toxicity is seen at the highest dose level, then the highest dosing regimen will be considered the MTD or the phase II RPTD.

• Up to 6 subjects will be enrolled at MTD to better define tolerability and safety before proceeding to the expanded cohort. ;

Related Conditions & MeSH terms

• Solid Tumors

• NCT number: NCT01485042
• Study type: Interventional
• Source: Duke University
• Status: Completed
• Phase: Phase 1
• Start date: December 2011
• Completion date: March 2014