Phase 1b/2 Study of U3-1287 in Combination With Trastuzumab Plus Paclitaxel in Newly Diagnosed Metastatic Breast Cancer (MBC)

NCT01512199 | Terminated Phase 1 DMC

• 1 other identifier: U31287-A-U202
• Study Type: interventional
• Target: 29
• Locations: 2 countries
• Sites: 8

Brief Summary

This is a Phase 1b/2 study. In Phase 1b portion, subjects will know the treatment they are receiving . Subjects will receive U3-1287 with trastuzumab plus paclitaxel . The phase 1b portion will determine if adding U3-1287 to trastuzumab plus paclitaxel will be safe in subjects with metastatic breast cancer. In phase 2 portion, subjects will be blinded to the treatments they are receiving . Subjects will receive either trastuzumab plus paclitaxel with U3-1287 or trastuzumab plus paclitaxel and placebo.The phase 2 portion will determine if adding U3-1287 to trastuzumab plus paclitaxel will be safe and improve survival in subjects with metastatic breast cancer.

Conditions

Metastatic Breast Cancer

Keywords

U3-1287; Trastuzumab; Paclitaxel; newly diagnosed HER-2 positive; breast cancer; metastatic

Outcome Measures

Primary Outcomes (2)

• Determination of the maximum tolerated dose based on the incidence of dose limiting toxicities (phase 1b only)

  The following criteria will also be considered a dose limiting toxicity (DLT). * \> 15% decrease in left ventricular ejection fraction (LVEF) from baseline or an LVEF value \> 10% below lower limit of normal (LLN) * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 x the upper limit of normal (ULN) AND total bilirubin \> 2 x ULN or international normalized ratio (INR) \> 1.5

  Study start to approximately 16 weeks

• Progression Free Survival (Phase 2 only)

  Tumor assessment will be conducted every 6 weeks independent of treatment cycle in accordance with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

  52 weeks (Start to end of Phase 2)

Secondary Outcomes (18)

• Pharmacokinetics (Area Under Curve) of U3-1287 when combined with trastuzumab plus paclitaxel

  Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

• Pharmacokinetics (Area Under Curve Extrapolation Percent) of U3-1287 when combined with trastuzumab plus paclitaxel

  Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

• Pharmacokinetics (C-max, C-min) of U3-1287 when combined with trastuzumab plus paclitaxel

  Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

• Pharmacokinetics (T-max) of U3-1287 when combined with trastuzumab plus paclitaxel

  Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

• Pharmacokinetics (Terminal Elimination Rate Constant) of U3-1287 when combined with trastuzumab plus paclitaxel

  Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

Study Arms (3)

U3-1287 with trastuzumab + paclitaxel (Phase 1b)

EXPERIMENTAL

The Phase 1b portion is an open label, dose de escalation, single arm study designed to assess the safety and tolerability of up to 3 dose levels of U3- 1287 in combination with trastuzumab plus paclitaxel and will determine the recommended Phase 2 dose (RP2D) of U3 1287. The first cohort will receive U3- 1287 18 mg/kg intravenously (IV) in combination with trastuzumab plus paclitaxel once every 3 weeks (q3w).

Drug: U3-1287; Drug: Trastuzumab; Drug: Paclitaxel

U3-1287 with trastuzumab+paclitaxel (Ph 2)

EXPERIMENTAL

The Phase 2 portion is a randomized, 2 arm, placebo controlled, double blind study designed to evaluate the safety and the efficacy of U3-1287 at the recommended phase 2 in combination with trastuzumab plus paclitaxel (experimental arm) relative to the control arm (trastuzumab plus paclitaxel and placebo).

Drug: U3-1287; Drug: Trastuzumab; Drug: Paclitaxel

Placebo with trastuzumab+paclitaxel (Ph 2)

PLACEBO COMPARATOR

The Phase 2 portion is a randomized, 2 arm, placebo controlled, double blind study designed to evaluate the safety and the efficacy of U3-1287 at the recommended phase 2 dose in combination with trastuzumab plus paclitaxel (experimental arm) relative to the control arm (trastuzumab plus paclitaxel and placebo).

Drug: Trastuzumab; Drug: Paclitaxel; Drug: Placebo

Interventions

Trastuzumab DRUG

Trastuzumab: 6 mg/kg up to 8 mg/kg administered intravenously once every three weeks

U3-1287 with trastuzumab + paclitaxel (Phase 1b)

Paclitaxel DRUG

Paclitaxel: 175 mg/m\^2 administered intravenously once every three weeks

U3-1287 with trastuzumab + paclitaxel (Phase 1b)

U3-1287 DRUG

U3-1287: 18 mg/kg administered intravenously once every three weeks

U3-1287 with trastuzumab + paclitaxel (Phase 1b)

Placebo DRUG

Placebo: Dose corresponding to U3-1287 administered intravenously once every three weeks

Placebo with trastuzumab+paclitaxel (Ph 2)

Eligibility Criteria

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

You may qualify if:

• Subjects must satisfy all of the following criteria to be included in the study:
• Women ≥ 18 years old.
• Histologically or cytologically confirmed adenocarcinoma of the breast with metastatic disease and at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines Version 1.1.
• Documented HER2+ disease as measured by FISH or IHC (3+). See Appendix 17.8 for documentation criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Hematological function, as follows:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count \>100 x 109/L
• Hemoglobin ≥9 g/dL.
• Renal function, as follows:
• \- Calculated creatinine clearance ≥60 mL/min using the modified Cockcroft Gault equation.
• Hepatic function, as follows:
• AST ≤2.5 x ULN (if liver metastases are present, \< 5 x ULN)
• ALT ≤2.5 x ULN (if liver metastases are present, \< 5 x ULN)
• Alkaline phosphatase ≤ 2.0 x ULN (if bone or liver metastases are present, \< 5 x ULN)

You may not qualify if:

• Subjects who meet any of the following criteria will be disqualified from entering the study:
• Prior treatment for metastatic disease other than radiation therapy. Neoadjuvant/adjuvant therapy with paclitaxel, and/or docetaxel, and/or trastuzumab is allowed if completed more than 12 months prior to relapse/progression.
• Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and require no treatment with steroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy.
• LVEF \< 50%. History of LVEF decline to \< 50% on prior trastuzumab therapy.
• Therapeutic or palliative radiation therapy or major surgery within 4 weeks before study drug treatment.
• History of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.
• Uncontrolled hypertension (diastolic blood pressure \> 100 mmHg or systolic blood pressure \> 140 mmHg). Use of antihypertensive medications is permissible to maintain blood pressure within the required parameters.
• Clinically significant electrocardiogram (ECG) changes that obscure the ability to assess the RR, PR, QT, QTc and QRS intervals.
• Subjects with left bundle branch block, atrial fibrillation and use of a cardiac pacemaker specifically will be excluded.
• Ascites or pleural effusion requiring chronic medical intervention.
• Pre-existing peripheral neuropathy \> grade 1.
• Myocardial infarction, symptomatic CHF (New York Heart Association \> Class II), unstable angina, or unstable cardiac arrhythmia requiring medication within 1 year before enrollment.
• Use of cytochrome P450 (CYP) 3A4 (CYP3A4) or CYP2C8 inducers within 28 days prior to Day 1, use of CYP3A4 or CYP2C8 inhibitors within 14 days prior to Day 1, or concurrent use of CYP3A4 or CYP2C8 inducers or inhibitors (see Appendix 17.6 for list of CYP34A and CYP2C8 inhibitors and inducers).
• Use of amiodarone within 6 months prior to enrollment.
• Concurrent use of antiarrhythmic medications.

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (8)

Unidad de Investigación FP Clinical Pharma en Centro Medico Integral Fitz Roy

Acevedo, Buenos Aires F.D., Argentina

Location

Centro Medico San Roque

San Miguel, Tucumán Province, T4000LAK, Argentina

Location

Hospital Britanico

Buenos Aires, 01280, Argentina

Location

Sanatorio de la Providencia

Buenos Aires, C1050AAK, Argentina

Location

Instituto Damic - Fundacion Rusculleda

Córdoba, X5003DCE, Argentina

Location

ISIS Centro Especializado

Santa Fe, S3000CVK, Argentina

Location

Instituto de Tereplas Oncologicas Providencia INTOP

Providencia, Santiago Metropolitan, Chile

Location

Hospital Clinico San Borja Arriaran

Santiago, Chile

Location

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

patritumab; Trastuzumab; Paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; 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; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2012
• First Posted: January 19, 2012
• Study Start: November 1, 2011
• Primary Completion: January 28, 2015
• Study Completion: January 28, 2015
• Last Updated: October 18, 2017

Record last verified: 2017-10

Locations

CL (2); AR (6)