GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer

NCT01918306 | Terminated Phase 1 Results DMC

• 2 other identifiers: VICC BRE 1287NCI-2013-01319
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 16

Brief Summary

This phase I/II trial study evaluates the tolerability and best tolerated dose of the PI3K inhibitor GDC-0941 when given with the chemotherapy cisplatin. This study will also examine how well the combination of GDC-0941 and cisplatin work in treating patients with androgen receptor negative triple negative metastatic breast cancer. Patients will be randomized to receive cisplatin alone or cisplatin with GDC-0941 in the phase II portion. Those receiving cisplatin alone can receive GDC-0941 upon progression of their disease. Cisplatin is a chemotherapy which has been shown to be effective in treating triple negative breast cancer. Preclinical studies show that adding a PI3K inhibitor such as GDC-0941 to cisplatin may be a more effective treatment for breast cancer.

Conditions

Estrogen Receptor Negative Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Triple Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer

Keywords

Triple Negative Breast Cancer; Estrogen receptor negative breast cancer; Metastatic breast cancer; Stage IV breast cancer; HER2 negative breast cancer

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose(MTD) of GDC-0941 and Recommended Phase II Dose of GDC-0941 Given in Combination With Cisplatin. - (Phase Ib)

  GDC-0941 dose will start at 260 mg (maximum dose). De-escalation of the intensity of the dose (if necessary) will proceed among cohorts of 3 patients according to a standard 3+3 algorithm beginning at the highest dose level of GDC-0941 260mg. MTD is defined as the highest dose at which a DLT is experienced \>= 1 out of 6 patients. A cohort of 3 patients was initially enrolled in the GDC-0941 arm at dose 260mg PO days 2-6, 9-13, 16-20, 23-27 of 28 day cycle 1. If no patient in the first cohort of 3 experiences a DLT, an additional cohort of 3 patients will be treated at the same dose level. 2. If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level. 3. If ≤1 patient has a DLT in 6 treated at this same dose, this will be considered a tolerable dose to move to phase II. 4. If 2 or more patients in 3 or 6 patients treated at a given dose experience DLT, the dose will be de-escalated to the next lower dose level.

  4 weeks

• Percentage of Patients Achieving Overall Response - (Phase II)

  The primary efficacy endpoint is overall response rate (ORR) of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- TN MBC. ORR is defined as the percentage of subjects achieving complete response (CR) plus partial response (PR) as their best response by RECIST version 1.1 for targeted lesions and assessed by CT, MRI scan. Objective responses, was estimated by the overall tumor burden at baseline (targeted lesions) in which subsequent measurements were performed every 8 weeks using the Solid Tumor Response Criteria (RECIST) v1.1 were compared. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  at 8 weeks

Secondary Outcomes (3)

• Number of Patients With Dose-limiting Toxicities Per NCI Common Terminology for Adverse Events (CTCAE) - (Phase Ib)

  During the first 4 weeks

• Clinical Benefit Rate - (Phase II)

  at 32 weeks

• Time to Progression - (Phase II)

  From time of randomization to disease progression, up to 104 weeks

Other Outcomes (1)

• Correlation of the Presence of PIK3CA Mutations in the Tumor With Time to Tumor Progression.

  2 years

Study Arms (5)

1PHIbA Arm A - cisplatin + GDC - 0941

EXPERIMENTAL

Determine the safety and tolerability of GDC-0941 given in combination with cisplatin in patients with AR- TN MBC. Determination of the maximally tolerated dose (MTD) of GDC-0941. Cohort 1, 3 of 3 patients received: Cisplatin 25 mg/m2 IV D1, 8, 15 GDC-0941 260 mg PO, days 2-6, 9-13, 16-20, 23-27, 28 day cycle GDC-0941 dose to start at Max dose of 260mg. If no patient in the first cohort of 3 experiences a DLT, an additional cohort of 3 patients will be treated at the same dose level. 1. If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level. 2. If ≤1 patient has a DLT in 6 treated at this same dose, this will be considered a tolerable dose to move to phase II If patients experience a DLT considered related to GDC-0941, the patient may remain on GDC-0941 and/or Cisplatin after resolution of the DLT. All such cases will be considered a DLT for the purposes of defining the MTD.

Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941

1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1

EXPERIMENTAL

If 2 or more patients in 3 or 6 patients treated at a given dose experience DLT, the dose will be de-escalated to the next lower dose level. Once the lowest dose level is reached, if a DLT occurs, the regimen will be considered too toxic and the corresponding cohort within the study will be discontinued. Determination of the maximally tolerated dose (MTD) of GDC-0941.

Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941

2PHII1 Arm 1 - Cisplatin

ACTIVE COMPARATOR

Evaluate the efficacy, as measured by the overall response rate (ORR), of Cisplatin +GDC-0941 versus Cisplatin alone in patients with AR- TN MBC. Patients will be randomized in a 1:1 fashion to arm 1: cisplatin, or arm 2: cisplatin + GDC-0941. Arm 1 Cisplatin Only Patient received: Cisplatin given intravenously (IV) over 1 hour for three consecutive weeks, then off one week (days 1, 8, and 15 of a 28 day cycle).

Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI

2PHII2 - Arm 2 - Cisplatin + GDC - 0941

EXPERIMENTAL

Evaluate the efficacy, as measured by the overall response rate (ORR), of Cisplatin +GDC-0941 versus Cisplatin alone in patients with AR- TN MBC. Patients are randomized in a 1:1 fashion to arm 1: cisplatin, or arm 2: cisplatin + GDC-0941. Arm 2 Cisplatin + GDC-0941 Patients received: Cisplatin given intravenously (IV) over 1 hour for three consecutive weeks, then off one week (days 1, 8, and 15 of a 28 day cycle). GDC-0941 260 mg PO, administered orally on days 2-6, 9-13, 16-20, 23-27 of a 28 day cycle.

Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941

2PHIICO

EXPERIMENTAL

Arm 2: Crossover post-progression Patients who are randomized to Cisplatin alone (Arm 1) can crossover to receive Cisplatin + GDC-0941 upon disease progression. Patient received: Cisplatin given intravenously (IV) over 1 hour for three consecutive weeks, then off one week (days 1, 8, and 15 of a 28 day cycle). GDC-0941 260 mg PO, administered orally on days 2-6, 9-13, 16-20, 23-27 of a 28 day cycle.

Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941

Interventions

cisplatin DRUG

In Arm I patients receive cisplatin IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may crossover to Arm II upon disease progression. In Arm II patients receive cisplatin as in Arm I and PI3K inhibitor GDC-0941 orally (PO) one time a day (QD) on days 2-6, 9-13, 16-20, and 23-27. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. \--------------------------------------------------------------------------------

Also known as: Platinol

1PHIbA Arm A - cisplatin + GDC - 0941; 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1; 2PHII1 Arm 1 - Cisplatin; 2PHII2 - Arm 2 - Cisplatin + GDC - 0941; 2PHIICO

laboratory biomarker analysis OTHER

correlative studies

1PHIbA Arm A - cisplatin + GDC - 0941; 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1; 2PHII1 Arm 1 - Cisplatin; 2PHII2 - Arm 2 - Cisplatin + GDC - 0941; 2PHIICO

pharmacological study OTHER

correlative studies

1PHIbA Arm A - cisplatin + GDC - 0941; 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1; 2PHII1 Arm 1 - Cisplatin; 2PHII2 - Arm 2 - Cisplatin + GDC - 0941; 2PHIICO

dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI PROCEDURE

correlative studies

1PHIbA Arm A - cisplatin + GDC - 0941; 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1; 2PHII1 Arm 1 - Cisplatin; 2PHII2 - Arm 2 - Cisplatin + GDC - 0941; 2PHIICO

GDC -0941 DRUG

Patients receive cisplatin as in Arm I and PI3K inhibitor GDC-0941 PO QD on days 2-6, 9-13, 16-20, and 23-27. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity

1PHIbA Arm A - cisplatin + GDC - 0941; 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1; 2PHII2 - Arm 2 - Cisplatin + GDC - 0941; 2PHIICO

Eligibility Criteria

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

You may qualify if:

• Patients must provide informed written consent.
• Patients must be \<18 years of age.
• ECOG performance status 0-1.
• Clinical stage IV invasive mammary carcinoma, ER negative (defined as expression of ER in \< 5% cells), PR negative (defined as expression of PR in \< 5% cells), HER2 negative \[acceptable FDA approved methods of HER2 analysis include IHC (0, 1+), fluorescence in situ hybridization (FISH) with HER2/CEN-17 ratio \<2, and/or chromogenic in situ hybridization (CISH)\] with HER2/CEN-17 ratio \<2, as previously documented by histological analysis.
• Androgen receptor negativity, defined as \< 10% of tumor cell nuclei with immunoreactivity for AR in a CLIA certified laboratory. See section 5.1.
• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension by RECIST criteria 1.1, with radiologic scans within 21 days of day 1, cycle 1.
• Up to one prior chemotherapy regimens for metastatic disease.
• No prior treatment with cisplatin in the metastatic setting.
• Biopsy of a metastatic lesion in patients with reasonably accessible metastatic lesions (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast, bones, lung, and liver metastases). If a reasonably accessible site is available for biopsy, the patient must agree to biopsy.
• Life expectancy ≥ 6 months in the opinion of the investigator
• Patients must have adequate hematologic, hepatic, and renal function. All tests must be obtained less than 21 days from day 1 of study treatment. This includes:
• ANC \>/=1500/mm3
• Platelet count \>/=100,000/mm3
• Hemoglobin ≥ 9 g/dL
• Creatinine \</=1.5X upper limits of normal (ULN)

You may not qualify if:

• Any kind of malabsorption syndrome significantly affecting gastrointestinal function.
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, biologic therapy) other than the ones specified in the protocol. Patients must have discontinued the above cancer therapies for 1 week prior to the first dose of study medication, as well as recovered from toxicity (to ≤ than grade 1, except for alopecia) induced by previous treatments. Any investigational drugs should be discontinued 2 weeks prior to the first dose of study medication and radiotherapy must have been completed ≥ 2 weeks prior to initiation of study drug (Cycle 1, Day 1).
• Prior use of PI3K, or Akt inhibitors in the neoadjuvant, adjuvant, and metastatic setting for the treatment of cancer. These include, but are not limited to: GDC-0941, GDC-0980, GDC-0032, BEZ235, BKM120, LY294002, PIK-75, TGX-221, XL147, XL765, SF1126, PX-866, D-87503, D-106669, GSK615, CAL101. Patients who have received PI3K/Akt inhibitors previously for \<4 weeks will be eligible.
• Pregnant or lactating women.
• Uncontrolled intercurrent illness including, but not limited to:
• Ongoing or active infection requiring parenteral antibiotics
• Impairment of lung function (COPD \> grade 2, lung conditions requiring oxygen therapy) or current dyspnea at rest
• Symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease)
• Known Left Ventricular Ejection Fraction (LVEF) \< 50%.
• Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
• Uncontrolled hypertension (systolic blood pressure \>160 mm Hg or diastolic blood pressure \> 100 mm Hg, found on two consecutive measurements separated by a 1 or 2 week period despite adequate medical support)
• Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment \[National Cancer Institute -Common Terminology Criteria for Adverse Events, Version 4.0, grade 3\]
• QTcF ≥ 480 msec on screening EKG
• Known history of QT/QTc prolongation or Torsades de Pointes (TdP)
• ST depression or elevation of ≥ 1.5 mm in 2 or more leads

Sponsors & Collaborators

• Vanderbilt-Ingram Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• Genentech, Inc.: collaborator

Study Sites (16)

University of Alabama

Birmingham, Alabama, United States

Location

University of California, San Francisco

San Francisco, California, United States

Location

Georgetown University

Washington D.C., District of Columbia, United States

Location

Emory University

Atlanta, Georgia, United States

Location

University of Chicago

Chicago, Illinois, United States

Location

Indiana University

Indianapolis, Indiana, United States

Location

John Hopkins University

Baltimore, Maryland, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Location

University of Michigan

Ann Arbor, Michigan, United States

Location

Mayo Clinic

Rochester, Minnesota, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Location

University of North Carolina

Charlotte, North Carolina, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Baylor Breast Center

Houston, Texas, United States

Location

University of Washington

Seattle, Washington, United States

Location

Related Links

• Vanderbilt-Ingram Cancer Center, Find a Clinical Trial

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Breast Neoplasms

Interventions

Cisplatin; 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Results Point of Contact

• Title: Dr. Vandana Abramson
• Organization: Vanderbilt-Ingram Cancer Center

vandana.abramson@vanderbilt.edu

800-811-8480

Study Officials

• Vandana G. Abramson, MD

  Vanderbilt-Ingram Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine; Medical Oncologist

Study Record Dates

• First Submitted: July 25, 2013
• First Posted: August 7, 2013
• Study Start: September 1, 2013
• Primary Completion: December 1, 2014
• Study Completion: April 1, 2015
• Last Updated: June 27, 2017
• Results First Posted: June 27, 2017

Record last verified: 2017-05

Locations

US (16)