NCT01386580

An Open-label, Phase I/IIa, Dose Escalating Study of 2B3-101 in Patients With Solid Tumors and Brain Metastases or Recurrent Malignant Glioma.

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 84 (actual)
• Sponsor: BBB-Therapeutics B.V. · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The purpose of this study is to determine the safety, tolerability, and pharmacokinetics (PK) of 2B3-101 both as single agent and in combination with trastuzumab. Furthermore, the study will explore the preliminary antitumor activity of 2B3-101 as single agent in patients with with solid tumors and brain metastases or recurrent malignant glioma as well as in patients with various forms of breast cancer with and in combination with trastuzumab in HER2+ breast cancer patients with brain metastases.

Detailed description

This is a Phase I/IIa, multicenter, open-label, dose-escalation study. The study will be conducted in 6 phases: "2B3-101 single agent dose-escalation phase", "a 2B3-101 with trastuzumab dose-escalation phase", "a Breast cancer brain metastases study-expansion phase","a Recurrent malignant glioma study-expansion phase", "a Melanoma brain metastases study- expansion phase" and "SCLC brain metastases study-expansion phase" 2B3-101 single agent dose-escalation phase. In the 2B3-101 single Agent dose-escalation phase, female and male patients with solid tumors and brain metastases or recurrent malignant glioma will be enrolled. Patients will be assigned to a dose level cohort. - The starting dose will be 5 mg/m2, which is equal to 1/10 of the human equivalent dose of the LD10 of 2B3-101 in rats. A "3+3" dose-escalation design will be used. The study will investigate sequential cohorts consisting of 3-6 patients to be enrolled and treated at the applicable dose level. Planned dose levels for subsequent cohorts are 10, 20, 30, mg/m2 and steps of 10 mg/m2 thereafter. For more information on the dose escalation design and the increments, please see the dose escalation criteria section. There will be no intra-patient dose escalation. Each treatment cycle consists of 21 days. Patients will receive a single IV dose of 2B3-101 on day 1 of each cycle. In order to minimize the risk of infusion reactions 5% of the total dose of 2B3-101 (in mg) should be infused slowly over the first 30 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes. Blood samples will be taken on day 1, 2, 3, 5, 8 and 11 of cycle 1 and day 1, 8 and 15 of cycle 2 to assess the PK profile during the first 2 cycles. The dose limiting toxicity (DLT) observation period for each dose level will be cycle 1 (day 1 to day 21). Patients who do not complete the DLT observation period (cycle 1) for other reasons than a DLT will be replaced. Once the MTD of 2B3-101 as single agent has been determined, the study will continue to the breast cancer brain metastases and recurrent malignant glioma dose expansion phases. 2B3-101 in combination with trastuzumab dose-escalation phase In the 2B3-101 in combination with trastuzumab dose escalation phase, only patients with HER2+ breast cancer and brain metastases will be enrolled. The patients will be assigned to a 2B3-101 dose level cohort. - The starting dose of 2B3-101 will be 40 mg/m2 every 3 weeks. This dose has been selected based upon safety information from patients treated with 2B3-101 at this dose level, as well as upon previous treatment with PEGylated liposomal doxorubicin in combinations trastuzumab (Chia et al 2006). The dose-escalation will be conducted in steps of 10 mg/m2 up to the MTD level determined for 2B3-101 as single agent. The trastuzumab dose will remain fixed to a loading dose of 8 mg/kg at day 1 and 6 mg/kg every 3 weeks at the subsequent cycles throughout the determination of the MTD. Enrolment of HER2+ patients breast cancer patients in the "2B3-101 in combination with trastuzumab dose-escalation" phase of the study will be allowed in parallel with the determination of the MTD of 2B3-101 as single agent. A "3+3" dose-escalation design will be used. Thus, the study will investigate sequential cohorts of 3-6 patients, who will be enrolled and treated at the applicable dose levels. No intra-patient dose-escalation will be allowed. Each treatment cycle consists of 21 days. All patients will receive a single IV dose of 2B3-101 on day 1 of each cycle. In order to minimize the risk of infusion reactions 5% of the total dose of 2B3-101 (in mg) should be infused slowly over the first 30 minutes. As long as 2B3-101 is well tolerated, the remaining 95% of the infusion could thereafter be administered over the next 60 min, resulting in a total infusion time of 90 minutes. The infusion of trastuzumab will then follow 30 minutes after the completion of the 2B3-101 infusion. Blood samples will be taken on day 1, 2, 3, 5, 8 and 11 of cycle 1, on day 1, 8 and 15 of cycle 2 and if applicable on day 1 of cycle 3 and day 1 of cycle 4 to assess the PK profile of 2B3-101 during the first 4 cycles. The dose limiting toxicity (DLT) observation period will be cycle 1 (day 1 to day 21) at each individual dose level. Patients who do not complete the DLT observation period (cycle 1) for other reasons than a DLT will be replaced. Breast cancer brain metastases expansion phase. In the breast cancer brain metastases expansion phase, each treatment cycle consists of 21 days. Patients will receive a single IV dose of 2B3-101 on day 1 of each cycle. In order to minimize the risk of infusion reactions 5% of the total dose of 2B3-101 (in mg) should be infused slowly over the first 30 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes. Blood samples will be taken on day 1, 2, 3, 5, 8 and 11 of cycle 1 on day 1, 8 and 15 of cycle 2 and if applicable on day 1 of cycle 3 and on day 1 of cycle 4 to assess the PK profile during the first 4 cycles. Recurrent malignant glioma expansion phase. In the recurrent malignant glioma expansion phase, each treatment cycle is 28 days long. Patients will receive a single IV dose of 2B3-101 on day 1 of each cycle. In order to minimize the risk of infusion reactions 5% of the total dose of 2B3-101 (in mg) should be infused slowly over the first 30 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes. Blood samples will be taken on day 1, 2, 3, 5, 8 and 11 of cycle 1, day 1, 8 and 15 of cycle 2 and if applicable on day 1 of cycle 3 and on day 1 of cycle 4 to assess the PK profile during the first 4 cycles. SCLC brain metastases study arm of the expansion phase In the SCLC brain metastases study arm of the expansion phase, each treatment cycle is 21 days long. Patients will receive a single IV dose of 2B3-101 at MTD determined for 2B3-101 as single agent on day 1 of each cycle. In order to minimize the risk of infusion reactions 5% of the total dose (in mg) should be infused slowly over the first 30 minutes. As long as 2B3-101 is well tolerated, the remaining 95% of the infusion could thereafter be administered over the next 60 minutes, resulting in a total infusion time of 90 minutes. Blood samples will be taken on day 1, 2, 3, 5, 8 and 11 of cycle 1, day 1, 8 and 15 of cycle 2 and if applicable on day 1 of cycle 3 and on day 1 of cycle 4 to assess the PK profile during the first 4 cycles. Melanoma brain metastases study arm of the expansion phase In the melanoma brain metastases study arm of the expansion phase, each treatment cycle is 21 days long. Patients will receive a single IV dose of 2B3-101 at MTD determined for 2B3-101 as single agent in the dose escalation phase on day 1 of each cycle. In order to minimize the risk of infusion reactions 5% of the total dose (in mg) should be infused slowly over the first 30 minutes. As long as 2B3-101 is well tolerated, the remaining 95% of the infusion could thereafter be administered over the next 60 minutes, resulting in a total infusion time of 90 minutes. Blood samples will be taken on day 1, 2, 3, 5, 8 and 11 of cycle 1, day 1, 8 and 15 of cycle 2 and if applicable on day 1 of cycle 3 and on day 1 of cycle 4 to assess the PK profile during the first 4 cycles. For all stages a patient will stay on treatment until disease progression, unacceptable toxicity, or discontinuation for any other reason.

Conditions

• Brain Metastases
• Lung Cancer
• Breast Cancer
• Melanoma
• Malignant Glioma

Interventions

Type	Name	Description
DRUG	2B3-101	IV every 21 days
DRUG	Trastuzumab	IV every 21 days
DRUG	2B3-101 60 mg/m2 every 4 weeks	IV every 28 days
DRUG	2B3-101 50 mg/m2 every 3 weeks	IV every 21 days

Timeline

• Start date: 2011-07-01
• Primary completion: 2014-12-01
• Completion: 2014-12-01
• First posted: 2011-07-01
• Last updated: 2015-01-22

Locations

10 sites across 4 countries: United States, Belgium, France, Netherlands