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

NCT01386580 | Completed Phase 1

• 1 other identifier: 2B3-101-CR-001
• Study Type: interventional
• Target: 84
• Locations: 4 countries
• Sites: 10

Brief 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.

Conditions

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

Keywords

Brain Neoplasms; Neoplasm Metastasis; Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplastic Processes; Pathologic Processes

Outcome Measures

Primary Outcomes (4)

• To characterize the safety and tolerability of intravenously administered 2B3-101 in patients with advanced solid tumors and metastatic brain cancer or recurrent malignant glioma.

  16 months

• To identify the maximum tolerated dose (MTD) of of intravenously administered 2B3-101 in patients with advanced solid tumors and metastatic brain cancer or recurrent malignant glioma.

  16 months

• To assess the safety and tolerability of intravenously (IV) administered 2B3-101 in combination with trastuzumab, in patients with HER2+ breast cancer with brain metastases

  9 months

• To identify the maximum tolerated dose (MTD) of of intravenously administered 2B3-101 in combination with trastuzumab in patients with HER2+ breast cancer with brain metastases

  9 months

Secondary Outcomes (12)

• Examine the pharmacokinetics (PK) in plasma of intravenously administered 2B3-101 in terms of Cmax, Vss, T1/2, AUC, CL;

  16 months

• Obtain preliminary information on the clinical anti-tumor activity of intravenously administered 2B3-101 on brain metastases secondary to breast cancer in terms of objective response rate.

  16 months

• Obtain preliminary information on the clinical anti-tumor activity of intravenously administered 2B3-101 on brain metastases secondary to breast cancer in terms of duration of response.

  16 months

• Obtain preliminary information on the clinical anti-tumor activity of intravenously administered 2B3-101 on recurrent malignant glioma in terms of objective response rate.

  16 months

• Obtain preliminary information on the clinical anti-tumor activity of intravenously administered 2B3-101 on recurrent malignant glioma in terms of duration of response.

  16 months

Study Arms (4)

2B3-101 Single Agent Dose Escalation

EXPERIMENTAL

Patients in single agent dose escalation arm 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.

Drug: 2B3-101

2B3-101 in combination with trastuzumab

EXPERIMENTAL

HER2+ breast cancer patients with brain metastases 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.

Drug: 2B3-101; Drug: Trastuzumab

2B3-101 solid tumor expansion

EXPERIMENTAL

Patients in the breast, Small Cell Lung Cancer and melanoma dose expansion arms 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.

Drug: 2B3-101 50 mg/m2 every 3 weeks

2B3-101 glioma expansion

EXPERIMENTAL

Patients in the single agent glioma dose expansion arm 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.

Drug: 2B3-101 60 mg/m2 every 4 weeks

Interventions

2B3-101 DRUG

IV every 21 days

Also known as: Glutathione pegylated liposomal doxorubicin hydrochloride

2B3-101 Single Agent Dose Escalation; 2B3-101 in combination with trastuzumab

Trastuzumab DRUG

IV every 21 days

Also known as: Herceptin

2B3-101 in combination with trastuzumab

2B3-101 60 mg/m2 every 4 weeks DRUG

IV every 28 days

Also known as: Glutathione pegylated liposomal doxorubicin hydrochloride

2B3-101 glioma expansion

2B3-101 50 mg/m2 every 3 weeks DRUG

IV every 21 days

Also known as: Glutathione pegylated liposomal doxorubicin hydrochloride

2B3-101 solid tumor expansion

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years.
• Measurable intracranial disease by MRI.
• ECOG Performance Status ≤ 2.
• Estimated life expectancy of at least 8 weeks.
• Toxicities incurred as a result of previous anticancer therapy (radiation therapy, chemotherapy, or surgery) must be resolved to ≤ grade 2 (as defined by CTCAE version 4.0).
• No evidence of (cortical) cognitive impairment as defined by a Mini-Mental Status Exam (MMSE) score ≥ 25/30.
• Written informed consent according to local guidelines.
• In addition to the above listed eligibility criteria, the following criteria are applicable:
• B3-101 single agent dose-escalation phase:
• Patients with pathologically confirmed diagnosis of advanced, recurrent solid tumors and unequivocal evidence of brain metastases that are refractory to standard therapy or for whom no standard therapy exists or with unequivocal evidence of newly diagnosed untreated brain metastases and controlled extracranial disease which per the multi-disciplinary team decision do not require immediate radiotherapy, surgery or standard systematic chemotherapy. Brain metastases may be stable, progressive, symptomatic or asymptomatic brain metastasis/es. Stable or decreasing dosage of steroids (e.g. dexamethasone) for 7 days prior to baseline MRI or non-enzyme inducing anti-epileptic drugs is allowed.
• Or -
• Patients with pathology confirmed diagnosis of advanced, recurrent primary malignant (grade III and IV) glioma that are refractory to standard therapy or for whom no standard therapy exists. Stable or decreasing dosage of steroids (e.g. dexamethasone) for 7 days prior to baseline MRI or non-enzyme inducing anti-epileptic drugs are allowed.
• B3-101 in combination with trastuzumab dose escalation phase:
• Patients with histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization \[FISH\] amplified; by clinical assay on either primary or metastatic tumor) adenocarcinoma of the breast with unequivocal evidence of brain metastases that are refractory to standard therapy or for which no standard therapy exist or with unequivocal evidence of newly diagnosed untreated brain metastases and controlled extracranial disease which per the multi-disciplinary team decision do not require immediate radiotherapy, surgery or standard systematic chemotherapy can be included to this escalation phase as well.
• \- Breast cancer brain metastases expansion phase:

You may not qualify if:

• Prior Treatment. 1. Less than 1 week since the last treatment of lapatinib, less than 2 weeks since the last treatment of vemurafenib, less than 4 weeks since the last treatment of chemotherapy, biological therapy, immunotherapy and systemic radiotherapy (except palliative radiation delivered to \<20% of bone marrow), less than 8 weeks for cranial radiotherapy, and less than 6 weeks for nitrosoureas and mitomycin C.
• \. Patients that have received a maximum cumulative dose of free (i.e., non-liposomal) or liposomal doxorubicin \> 360mg/m2 or free epirubicin \> 600mg/m2.
• Current Treatment. 3. Current or recent (within 30 days of first study treatment) treatment with another investigational drug or participation in another investigational study.
• Hematology, coagulation and biochemistry. 4. Inadequate bone marrow function: Absolute Neutrophil Count (ANC): \< 1.5 x 109/L, or platelet count \< 100 x 109/L or hemoglobin \< 6 mmol/L.
• \. Inadequate liver function, defined as:
• Serum (total) bilirubin \> 1.5 x the ULN for the institution if no liver metastases (\> 2 x ULN in patients with liver metastases);
• ASAT or ALAT \> 2.5 x ULN if no liver metastases (\> 4 x ULN in patients with liver metastases);
• Alkaline phosphatase levels \> 2.5 x ULN if no liver metastases (\> 5 x ULN in patients with liver metastases, or \> 10 x ULN in patients with bone metastases).
• \. Inadequate renal function, defined as:
• Serum creatinine \> 1.5 x ULN.
• Other. 7. Leptomeningeal carcinomatosis as the only site of CNS involvement. 8. Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior to study treatment start, or within 14 days followed by a confirmatory urine pregnancy test within 7 days prior to study treatment start.
• \. For female subjects of childbearing potential (defined as \< 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel).
• \. Major surgical procedure (including open biopsy, excluding central line IV and portacath) within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment.
• \. Grade 3 or 4 motor, sensory, or cranial neuropathy symptoms (as defined by CTCAE version 4.0).
• \. Uncontrolled hypertension (systolic \> 150 mm Hg and/or diastolic \> 100mm Hg).

Sponsors & Collaborators

• BBB-Therapeutics B.V.: lead

Study Sites (10)

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Universitair Ziekenhuis Antwerpen

Antwerp, B-2650, Belgium

Location

Jules Bordet Institute

Brussels, B-1000, Belgium

Location

Institut Curie

Paris, Paris Cedex 05, 75248, France

Location

Institut Gustave Roussy

Villejuif, Val de Marne, 94805, France

Location

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, 1066 CX, Netherlands

Location

Vrije Universiteit medisch centrum (Vumc)

Amsterdam, 1081 HV, Netherlands

Location

Leids Universitair Medisch Centrum (LUMC)

Leiden, 2333 CA, Netherlands

Location

Maastricht Universitair Medisch Centrum

Maastricht, 6229 HX, Netherlands

Location

Erasmus MC

Rotterdam, 3075 EA, Netherlands

Location

MeSH Terms

Conditions

Brain Neoplasms; Lung Neoplasms; Breast Neoplasms; Melanoma; Glioma; Neoplasm Metastasis; Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplastic Processes; Pathologic Processes

Interventions

glutathione pegylated liposomal doxorubicin; Trastuzumab

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms, Neuroepithelial; Neoplasms, Glandular and Epithelial; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• J. Veeneman, PhD

  BBB Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2011
• First Posted: July 1, 2011
• Study Start: July 1, 2011
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: January 22, 2015

Record last verified: 2015-01

Locations

FR (2); BE (2); US (1); NL (5)