Dasatinib In Combination With Trastuzumab And Paclitaxel In First Line Treatment Of Her2-Positive MBC Patients

NCT01306942 | Completed Phase 1 Results

• 2 other identifiers: GEICAM/2010-042010-023304-27
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 8

Brief Summary

This is a single-arm, open-label, phase I/II study. In the phase I, patients with Human Epidermal Growth Factor Receptor 2 (HER2) positive MBC will be treated with paclitaxel, trastuzumab and increasing doses of dasatinib to determine the Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) and Recommended Phase II Dose (RPD) of the combination. Once the RPD has been identified, 48 patients will be treated at that dose to evaluate the efficacy and safety of the combination in the phase II.

Conditions

Metastatic Breast Cancer

Keywords

HER2 positive breast cancer; first line treatment; Dasatinib; SRC kinase; Trastuzumab resistance

Outcome Measures

Primary Outcomes (4)

• Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I)

  DLT was defined as the occurrence of any of the following adverse events or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03), assessed as possibly, probably or definitively related to study drugs, occurring within the first cycle of study treatment: Need of any dose modification within the first cycle due to toxicity, grade 3 or 4 neutropenia complicated with fever ≥38.5° C or infection, grade 4 neutropenia (absolute neutrophil count (ANC)\<0.5x1000000000/L) of at least 7 days duration, grade 3 thrombocytopenia complicated by hemorrhage, grade 4 thrombocytopenia, any grade 4 non-hematologic toxicity, grade 3 non-hematologic toxicities except nausea, vomiting, or diarrhea that can be controlled by appropriate medical intervention or prophylaxis, inability to resume dosing for cycle 2 at the current dose level within 14 days due to treatment related toxicity.

  Up to cycle 1

• Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I)

  MTD is determined by testing increasing doses of dasatinib on dose escalation cohorts 3 to 6 patients per dose level. MTD reflects the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels

  Up to cycle 1

• Recommended Phase II Dose (RP2D) of Dasatinib in Combination With Trastuzumab and Paclitaxel (Phase I).

  The RP2D was decided by the investigators taken into consideration the information obtained in the study and based on the MTD. To define the RP2D, information about toxicity observed during the full treatment were taken into consideration (relative dose intensity and toxicity observed).

  Up to cycle 1

• Objective Response Rate (ORR)

  Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients who had measurable disease at baseline. Per RECIST, Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  Through study treatment, an average of 24 months

Secondary Outcomes (16)

• The Number of Participants Who Experienced Adverse Events (AE)

  Through study treatment, an average of 24 months

• To Evaluate the Clinical Benefit Rate (CBR)

  Through study treatment, an average of 24 months

• Time to Progression (TTP)

  Through study treatment, an average of 24 months

• Progression Free Survival (PFS)

  Through study treatment, an average of 24 months

• Response Duration (RD)

  Through study treatment, an average of 24 months

Study Arms (1)

Dasatinib + trastuzumab + paclitaxel

EXPERIMENTAL

Eligible patients will be enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib will be administered orally in two dose levels 100 and 140 mg once daily (QD) (a -1 dose level is included just in case dose de-escalation is needed). Treatment will be repeated on Day 1 of a 28-day cycle until radiographic or symptomatic progression or unacceptable toxicity occurs. Only in the phase I, the first cycle will last 38 days.

Drug: Dasatinib; Drug: Trastuzumab; Drug: Paclitaxel

Interventions

Dasatinib DRUG

Also known as: Sprycel

Dasatinib + trastuzumab + paclitaxel

Trastuzumab DRUG

Also known as: Herceptin

Dasatinib + trastuzumab + paclitaxel

Paclitaxel DRUG

Also known as: Taxol

Dasatinib + trastuzumab + paclitaxel

Eligibility Criteria

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

You may qualify if:

• Female with histologically confirmed breast cancer with documented metastasis.
• Patients must have Human Epidermal Growth Factor Receptor 2 (HER2) overexpression by immunohistochemistry (3+, HercepTest®; DAKO) or a positive fluorescence in situ hybridization for HER2 amplification evaluated by central laboratory. It is recommended that a formalin-fixed paraffin embedded (FFPE) tumor tissue block from the metastatic site (or the primary tumor, if metastatic site not available) required for HER2 testing are provided.
• Patients can have measurable or non measurable disease for the Phase I part. For the Phase II only patients with measurable disease defined per RECIST 1.1 will be included.
• Signed Written Informed Consent.
• Target Population:
• Patients with Performance Status (ECOG) of 0 or 1.
• Number of previous therapies allowed or previous therapies may have included:
• Chemotherapy: no prior chemotherapy for MBC is permitted. Patients treated with adjuvant chemotherapy regimens based on taxanes are allowed to be included if they are fully recovered of any taxane associated toxicity and a minimum of 12 months have elapsed from the end of this therapy.
• Hormonal Therapy: patients may have had prior hormonal therapy. All hormonal agents must be discontinued at least 3 weeks prior to study entry.
• Radiation Therapy: patients may have had prior radiation therapy that has not exceeded 25% of the bone marrow reserve. A minimum of 21 days must have elapsed between the last dose of radiation and registration into the study. Patients must have recovered from any acute toxic effects from radiation prior to registration. Lesions that have been irradiated cannot be included as sites of measurable disease for the phase II unless clear tumor progression, according to RECIST criteria, has been documented in these lesions since the end of radiation therapy.
• Previous Surgery: previous surgery is permitted provided that wound healing has occurred.
• Anti-HER2 Therapies: no prior anti-HER2 therapy for MBC is permitted. Patients treated with adjuvant anti-HER2 therapies (including but not limited to trastuzumab and lapatinib) are allowed to be included if a minimum of 12 months have elapsed from the end of this therapy.
• Adequate Organ Function (...).
• Ability to take oral medication (dasatinib must be swallowed whole).
• Concomitant Medications

You may not qualify if:

• Sex and reproductive status:
• WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug
• Women who are pregnant or breastfeeding.
• Women with a positive pregnancy test
• Target Disease Exceptions:
• a) Central nervous system (CNS) metastases which are not well controlled. Eligible patients must be asymptomatic, cannot be receiving steroids or anticancer treatment, and must be enrolled at least 1 month after the end of the radiotherapy treatment
• Medical History and Concurrent Diseases
• No malignancy \[other than the one treated in this study\] which required radiotherapy or systemic treatment within the past 5 years.
• Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion of any grade.
• i) Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within (6 months) ii). Patients with intercurrent cardiac dysfunction or left ventricular ejection fraction (LVEF) \< 50%.
• iii) Diagnosed congenital long QT syndrome. iv) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
• v) Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (450 msec).
• vi) Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.
• d) History of significant bleeding disorder unrelated to cancer, including: i) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease). ii) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).
• iii) Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding.

Sponsors & Collaborators

• Spanish Breast Cancer Research Group: lead
• Bristol-Myers Squibb: collaborator

Study Sites (8)

Instituto Catalán de Oncología de Barcelona (Hospital Duran i Reynalds)

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Hospital Alvaro Cunqueiro

Vigo, Pontevedra, 36204, Spain

Location

Complejo Hospitalario Universitario A Coruña

A Coruña, 15006, Spain

Location

Hospital Clinic i Provincial

Barcelona, 08036, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital Clínico Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Instituto Valenciano de Oncología

Valencia, 46009, Spain

Location

Related Publications (2)

• Ocana A, Gil-Martin M, Antolin S, Atienza M, Montano A, Ribelles N, Urruticoechea A, Falcon A, Pernas S, Orlando J, Montero JC, Escudero MJ, Benito S, Caballero R, Carrasco E, Rojo F, Pandiella A, Ruiz-Borrego M. Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study. Breast Cancer Res Treat. 2019 Apr;174(3):693-701. doi: 10.1007/s10549-018-05100-z. Epub 2019 Jan 3.

  PMID: 30607629 RESULT

• Ocana A, Gil-Martin M, Martin M, Rojo F, Antolin S, Guerrero A, Trigo JM, Munoz M, Pandiella A, Diego NG, Bezares S, Caballero R, Carrasco E, Urruticoechea A. A phase I study of the SRC kinase inhibitor dasatinib with trastuzumab and paclitaxel as first line therapy for patients with HER2-overexpressing advanced breast cancer. GEICAM/2010-04 study. Oncotarget. 2017 Apr 14;8(42):73144-73153. doi: 10.18632/oncotarget.17113. eCollection 2017 Sep 22.

  PMID: 29069857 RESULT

Related Links

• Spanish Breast Cancer Research Group (GEICAM) is a Spanish Breast Cancer Research Group

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Dasatinib; Trastuzumab; Paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; 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; Diterpenes; Terpenes

Results Point of Contact

• Title: Scientific Director / Medical Lead / Project Manager
• Organization: Spanish Breast Cancer Research Group

geicam@geicam.org

+34916592870

Study Officials

• Study Director

  Complejo Hospitalario Universitario de Albacete

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: February 24, 2011
• First Posted: March 2, 2011
• Study Start: July 1, 2011
• Primary Completion: December 1, 2013
• Study Completion: March 15, 2019
• Last Updated: March 30, 2023
• Results First Posted: September 9, 2019

Record last verified: 2023-03

Locations

ES (8)