Dose-Escalation Study of TH-302 in Combination With Sunitinib to Treat Patients With Advanced Renal Cell Carcinoma,Gastrointestinal Stromal Tumors and Pancreatic Neuroendocrine Tumors — TH-CR-410  

Gastrointestinal Stromal Tumors Clinical Trial

Official title: A Phase 1 Dose-Escalation Study to Determine the Safety of TH-302 in Combination With Sunitinib in Patients With Advanced Renal Cell Carcinoma,Gastrointestinal Stromal Tumors and Pancreatic Neuroendocrine Tumors

Status Unknown status

Clinical Trial Summary

The primary objectives are:

Dose escalation:

1. To determine the MTD and DLT(s) of TH-302 when used in combination with sunitinib.

Dose expansion:

1. To make a preliminary assessment of the efficacy of TH-302 in combination with sunitinib as determined by the response rate and the progression-free survival in subjects with advanced RCC treated at the RP2D

2. To assess the safety of TH-302 in combination with sunitinib and determine a recommended Phase 2 dose of the combination.

The secondary objectives are:

Dose expansion:

1. To make a preliminary assessment of the efficacy of TH-302 in combination with sunitinib as determined by stable disease or better rate, duration of response and overall survival in subjects with advanced RCC treated at the RP2D.

The exploratory objective is:

1. To explore the association of serum hypoxia biomarkers with efficacy endpoints.

Clinical Trial Description

This Phase 1 dose-escalation study will use a classic dose escalation design to determine the MTD of TH-302 when used in combination with sunitinib. The study will be divided into two parts completed in succession to determine the recommended phase 2 dose (RP2D) for dose expansion.

Part A:

The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. A Dose Level minus 1 and 2 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue with approximately 40% increases from the previous dose level; however lower dose increases of 20-39% may be implemented after consultation between the Investigators, Medical Monitor and Sponsor with the percent increase dependent on the current dose level and the cumulative safety data.

If a subject experiences a DLT, 3 additional subjects will be enrolled at that dose level for a total of 6 subjects in that cohort. If no additional DLTs are observed, dose escalation will resume. However, if 2 or more of 6 subjects within a cohort experience a DLT, that dose will be considered to exceed the MTD. The MTD will then be defined at the next lower dose level whereby 6 subjects were treated and < 1 subject experienced a DLT. The maximum dose of TH-302 will be 575 mg/m2.

The MTD will be based on toxicities occurring during the first cycle.

TH-302 will be administered by IV infusion over 30-60 minutes on Days 8, 15 and 22 of a 42-day cycle (6 weeks).

The dose of sunitinib will remain fixed: 50 mg administered PO daily on days 1 to 28 day of a 42-day cycle (6 weeks). On days when both sunitinib and TH-302 are administered, sunitinib should be administered at least 2 hours before or at least 2 hours after completion of the TH-302 dose.

Part B:

Once the MTD from Part A has been determined, Part B can commence.

The initial dose of TH-302 will be one dose level higher than the MTD established in Part A. The dose of TH-302 will be escalated in cohorts of 3-6 subjects. A Dose Level at the MTD established in Part A will be built into the study in the event that subjects experience excessive toxicity at the initial dose. Dose escalation will continue with approximately 40% increases from the previous dose level; however lower dose increases of 20-39% may be implemented after consultation between the Investigators, Medical Monitor and Sponsor with the percent increase dependent on the current dose level and the cumulative safety data.

If a subject experiences a DLT, 3 additional subjects will be enrolled at that dose level for a total of 6 subjects in that cohort. If no additional DLTs are observed, dose escalation will resume. However, if 2 or more of 6 subjects within a cohort experience a DLT, that dose will be considered to exceed the MTD. The MTD will then be defined at the next lower dose level whereby 6 subjects were treated and < 1 subject experienced a DLT.

The MTD will be based on toxicities occurring during the first cycle.

TH-302 will be administered by IV infusion over 30-60 minutes on Days 8, 15 and 22 of a 42-day cycle (6 weeks).

The dose of sunitinib will remain fixed: 37.5 mg administered PO daily on days 1 to 28 of a 42-day cycle (6 weeks).

On days when both sunitinib and TH-302 are administered, sunitinib should be administered at least 2 hours before or at least 2 hours after completion of the TH-302 dose.

An additional 10 RCC subjects will be enrolled at the recommended phase 2 dose (RP2D) for the dose expansion portion of the study. ;

Related Conditions & MeSH terms

• Advanced Renal Cell Carcinoma
• Carcinoid Tumor
• Carcinoma
• Carcinoma, Renal Cell
• Gastrointestinal Stromal Tumors
• Neoplasms
• Neuroendocrine Tumors
• Pancreatic Neuroendocrine Tumors

• NCT number: NCT01381822
• Study type: Interventional
• Source: Threshold Pharmaceuticals
• Status: Unknown status
• Phase: Phase 1
• Start date: June 2011
• Completion date: June 2014