Phase 2, Endocrine Therapy + OSI-906 With or Without Erlotinib for Hormone-sensitive Metastatic Breast Cancer - Full Text View

Purpose

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole +/- goserelin (the latter for pre-menopausal women only) may fight breast cancer by lowering the amount of estrogen the body makes. OSI-906 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether hormone therapy and OSI-906 are more effective when given with or without erlotinib hydrochloride in treating hormone-sensitive metastatic breast cancer.

PURPOSE: This phase II trial is studying how well giving hormone therapy together with OSI-906 with or without erlotinib hydrochloride works in treating hormone-sensitive patients with metastatic breast cancer.

Condition	Intervention	Phase
Breast Cancer	Drug: IGF-1R inhibitor OSI-906 Drug: erlotinib hydrochloride Drug: goserelin Drug: letrozole	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Trial of Endocrine Therapy in Combination With OSI-906 (an IGF-1R Inhibitor) With or Without Erlotinib (Tarceva, an EGFR Inhibitor) in Patients With Hormone-sensitive Metastatic Breast Cancer.

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Goserelin Insulin-like growth factor I Letrozole Goserelin acetate Erlotinib hydrochloride Erlotinib Mecasermin rinfabate

U.S. FDA Resources

Further study details as provided by Vanderbilt-Ingram Cancer Center:

Primary Outcome Measures:

Time to progression [ Time Frame: from study entry to date of progressive disease ] [ Designated as safety issue: No ]
Duration from study enrollment to date of progressive disease (PD) as measured by Response Evaluation in Solid Tumors (RECIST) criteria v. 1.1: measurable lesions: PD is > 20% increase in the sum of the longest diameter of target lesions or appearance of new lesions

Secondary Outcome Measures:

Safety profile of OSI-906 and letrozole +/ goserelin, with and without erlotinib [ Time Frame: at 4 weeks ] [ Designated as safety issue: Yes ]
The number of patients with worst-grade toxicity at each of five grades following NCI Common Toxicity Criteria: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, disabling, 5 = death
Response [ Time Frame: every 12 weeks to progression ] [ Designated as safety issue: No ]
Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions
Circulating C-peptide, IGF-1 [ Time Frame: At baseline and on day 1 of each 28-day cycle ] [ Designated as safety issue: No ]
Levels of the protein C-peptide and the hormone IGF-1 in the blood
Correlation of IGF-IR, EGFR, HER2, Y1316 and Y1131 pIGF-1R, PTEN, S473 pAkt, pMAPK, S118 (MAPK site), and S167 (Akt and S6 site) pER expression with time to progression and molecular classification [ Time Frame: On receipt of breast tissue: tissue block from prevous surgery or fresh tissue from current surgery ] [ Designated as safety issue: No ]
The levels of these biomarkers will be measured in breast tumor tissue and compared and contrasted with patient's time to progression and molecular classification (luminal A vs. luminal B)
Mutation analysis of PI3K (E542K, E545K, H1047R) [ Time Frame: On receipt of breast tissue: tissue block from prevous surgery or fresh tissue from current surgery ] [ Designated as safety issue: No ]
Breast tumor tissue will be examined for mutations in these genes.

Enrollment:	0
Study Start Date:	August 2009
Study Completion Date:	December 2009
Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Letrozole +/-goserelin, OSI-906 (Arm I ) Patients receive oral letrozole once daily on days 1-28 plus subcutaneous goserelin (the latter for pre-menopausal women only) on day 1 and oral IGF-1R inhibitor OSI-906 twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: IGF-1R inhibitor OSI-906 Given orally Drug: goserelin Given subcutaneously Other Name: Zoladex Drug: letrozole Given orally Other Name: Femara
Experimental: Letrozole +/- goserelin, OSI-906, erlotinib (Arm II) Patients receive oral letrozole and subcutaneous goserelin (the latter for pre-menopausal women only) and oral IGF-1R inhibitor OSI-906 as in arm I. Patients also receive oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: IGF-1R inhibitor OSI-906 Given orally Drug: erlotinib hydrochloride Given orally Other Name: Tarceva Drug: goserelin Given subcutaneously Other Name: Zoladex Drug: letrozole Given orally Other Name: Femara

Detailed Description:

OBJECTIVES:

Primary

To determine the antitumor activity of letrozole +/- goserelin (the latter for pre-menopausal women only) in combination with IGF-1R inhibitor OSI-906 with or without erlotinib hydrochloride, measured by time to progression, in patients with hormone-sensitive metastatic breast cancer.

Secondary

To determine the safety of these regimens in these patients.
To determine the response rate in patients treated with these regimens.
To measure circulating C-peptide, IGF-1, and IGFBP-3 levels in patients treated with these regimens.
To correlate the expression of IGF-IR, EGFR, HER2, Y1316 and Y1131 pIGF-1R, PTEN, S473 pAkt, pMAPK, S118 (MAPK site), and S167 (Akt and S6 site) pER in formalin-fixed paraffin blocks (FFPB) with clinical outcome and luminal A vs. luminal B subtypes of breast cancer.
To correlate the mutational status of PI3K (E542K, E545K, H1047R) in DNA extracted from FFPB or fresh biopsy with clinical outcome and luminal A vs. luminal B subtypes of breast cancer

OUTLINE: This is a multicenter study. Stratification will be based on previous exposure to endocrine therapy: (Arm I) no previous endocrine therapy or have completed adjuvant therapy > 6 months prior to study enrollment; (Arm II) patients that had previous endocrine therapy in the metastatic setting or had metastatic recurrence within 6 months of adjuvant endocrine therapy.

Arm I: Patients receive oral letrozole once daily on days 1-28 +/- subcutaneous goserelin* on day 1 and oral IGF-1R inhibitor OSI-906 twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Arm II: Patients receive oral letrozole +/- subcutaneous goserelin* and IGF-1R inhibitor OSI-906 as in arm I. Patients also receive oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Goserelin will only be given to premenopausal patients.

Tumor tissue samples from original diagnosis or from fresh biopsy tissue are collected for biomarker analysis and other studies.

After completion of study therapy, patients are followed periodically.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed invasive breast carcinoma
- Stage IV disease
No locally recurrent resectable disease
No symptomatic brain metastases
- History of brain metastases allowed provided the patient is clinically stable for > 3 weeks after completion of radiotherapy AND is not taking steroids or therapeutic anticonvulsants that are CYP3A4 modifiers
Hormone receptor status:
- Estrogen receptor and/or progesterone receptor positive tumor by immunohistochemistry (IHC)

PATIENT CHARACTERISTICS:

Pre- or post-menopausal
ECOG performance status 0-1
Life expectancy ≥ 6 months
ANC ≥ 1,250/mm^3
Platelet count ≥ 100,000/mm^3
Creatinine ≤ 1.5 times upper limit of normal (ULN)
Bilirubin ≤ 1.5 times ULN (≤ 3 times ULN if liver metastasis is present)
- For patients with Gilbert syndrome, direct bilirubin will be measured instead of total bilirubin
SGOT and SGPT ≤ 1.5 times ULN (≤ 3 times ULN if liver metastasis is present)
Alkaline phosphatase ≤ 1.5 times ULN (≤ 3 times ULN if liver metastasis is present)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier contraception during and for 3 months after completion of study therapy
Able to swallow and retain oral medication
Baseline QTc ≤ 450 msec
No other invasive cancer within the past 5 years except for completely resected basal cell or squamous cell skin cancer or successfully treated cervical carcinoma in situ
No malabsorption syndrome significantly affecting gastrointestinal function
No diabetes, fasting glucose > 150mg/dL, or receiving ongoing anti-hyperglycemic therapies
No concurrent uncontrolled illness including, but not limited to, any of the following:
- Ongoing or active infection requiring parenteral antibiotics
- Impaired lung function (i.e., COPD or lung conditions requiring oxygen therapy)
- Symptomatic congestive heart failure (NYHA class III or IV heart disease)
- Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within the past 6 months
- Uncontrolled hypertension, defined as systolic BP > 180 mm Hg or diastolic BP > 100 mm Hg on two consecutive measurements taken ≥ 1 week apart, despite adequate medical support
- Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia that is symptomatic or requires treatment)
- Psychiatric illness and/or social situation that would compromise patient safety or limit compliance with study requirements, including maintenance of a compliance/pill diary

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from prior therapy
At least 2 weeks since prior investigational drugs
No more than 4 prior chemotherapy treatments in the metastatic setting
- Does not include endocrine therapy or single-agent biologic therapy
No concurrent CYP3A4 or CYP1A2 modifiers
No other concurrent anticancer therapy, including chemotherapy, radiotherapy, surgery, immunotherapy, hormonal therapy, or biologic therapy
- Concurrent radiotherapy to painful bone metastases or areas of impeding bone fracture allowed provided radiotherapy is initiated before study therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01013506

Sponsors and Collaborators

Vanderbilt-Ingram Cancer Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Ingrid Mayer, MD

Vanderbilt-Ingram Cancer Center

More Information

No publications provided

Responsible Party:	Ingrid Mayer, MD, Assistant Professor of Medicine; Clinical Director, Breast Cancer Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:	NCT01013506 History of Changes
Other Study ID Numbers:	VICC BRE 0977, P30CA068485, VU-VICC-BRE-0977
Study First Received:	November 12, 2009
Last Updated:	May 22, 2013
Health Authority:	United States: Vanderbilt University Human Research Protection Program

Keywords provided by Vanderbilt-Ingram Cancer Center:

estrogen receptor-positive breast cancer
progesterone receptor-positive breast cancer
stage IV breast cancer
recurrent breast cancer

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Goserelin
Letrozole
Erlotinib

Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on June 13, 2013