Tipifarnib and Fulvestrant in Hormone Receptor-Positive Metastatic Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00082810
• Collaborator: (none)
• Enrollment: 33
• Location: 1
• Arm: 1
• Duration (Months): 54
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving tipifarnib together with fulvestrant works as second-line therapy in treating postmenopausal women with hormone receptor-positive inoperable locally advanced or metastatic breast cancer that has progressed after previous first-line endocrine therapy. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen. Combining tipifarnib with fulvestrant may kill tumor cells that did not respond to first-line therapy.

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor-positive Breast Cancer; Recurrent Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer	Drug: fulvestrant; Drug: tipifarnib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the efficacy of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant based on clinical benefit rate (CBR, a combination of complete response rate, partial response rate, and stable disease for more than 24 weeks) in postmenopausal women with hormone receptor-positive metastatic breast cancer who have progressive disease after first-line endocrine therapy.

SECONDARY OBJECTIVES:

1. To determine the median time to progression (TTP) and duration of response of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant in postmenopausal women with hormone receptor-positive metastatic breast cancer.

2. To determine the median overall survival of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant in postmenopausal women with hormone receptor- positive metastatic breast cancer who have progressive disease after first-line endocrine therapy.

3. To determine the toxicity profile of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant versus fulvestrant alone (from historical control) in postmenopausal women with hormone receptor positive metastatic breast cancer who have progressive disease after first-line endocrine therapy.

OUTLINE:

Patients receive fulvestrant intramuscularly on day 1 and oral tipifarnib twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity*.

NOTE: *Fulvestrant continues even if tipifarnib is held for toxicity.

Patients are followed every 3 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Tipifarnib (R115777, Zarnestra™) in Combination With Fulvestrant (Faslodex®) in Postmenopausal Hormone Receptor-Positive Breast Cancer
• Study Start Date: Mar 1, 2004
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (tipifarnib, fulvestrant) Patients receive fulvestrant intramuscularly on day 1 and oral tipifarnib twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity*.	Drug: fulvestrant; Given intramuscularly; Other Names: Faslodex ICI 182,780 ; Drug: tipifarnib; Given IV; Other Names: R115777 Zarnestra

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate (CBR) (CR Rate, PR Rate, and SD) [Up to 24 weeks]

   Number of participants met the definition of Clinical Benefit Rate.Tumor response was assessed every three cycles by CT using RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Per Response Evaluation Criteria in Solid Tumors (RECIST 1.0) for target lesions: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

Secondary Outcome Measures

1. Time to Progression (TTP) [From randomization until progression of the disease, assessed up to 4 years]

   TTP was estimated using the Kaplan-Meier method.

2. Duration of Response [Up to 4 years]

   DOR was defined for responders as the time from the onset of first response to disease progression and for non-responders as zero

3. Toxicity as Assessed by NCI CTCAE Version 3.0 [Up to 4 years]

   Number of Participants with serious (grade 3) or life-threatening (grade 4) adverse events

4. Median Overall Survival [From randomization until death or censored at the date of last follow-up, assessed up to 4 years]

   The 95% confidence intervals will be used.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed adenocarcinoma of the breast

• Patients must be postmenopausal

• Patients must have stage IV disease or inoperable locally advanced disease

• Patients must have ER- and/or PR-positive disease as determined by their local pathology laboratory

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan; all sites of disease should be noted and followed

• Prior hormonal therapy as adjuvant therapy and/or for metastatic disease is permitted; patients previously treated with two or more prior doses of fulvestrant are not eligible; patients who have received one prior dose of fulvestrant within 28 days are eligible so long as they meet other eligibility criteria

• Patients must have ECOG performance status 0-2 (Karnofsky >= 60%)

• Patients must have life expectancy of greater than 3 months

• Leukocytes >= 3,000/uL

• Absolute neutrophil count >= 1,500/uL

• Platelets >= 100,000/uL

• Total bilirubin =< 2 mg/dL

• AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal

• Creatinine less than or equal to 1.5 times the institutional upper limits of normal

• Patients must be disease-free of prior invasive malignancies for >= 5 years with the exception of: curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix

• Patients must have the ability to understand and the willingness to sign a written informed consent document

• Patients who have had previous therapy with farnesyltransferase inhibitor

Exclusion Criteria:

• Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; patients who have had prior chemotherapy for metastatic disease are not eligible; prior adjuvant or neoadjuvant chemotherapy is allowed

• Patients may not be receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to tipifarnib (R115777, Zarnestra™) or other agents used in the study (e.g., imidazoles, quinolones)

• Presence of rapidly progressive, life-threatening metastases; this includes patients with extensive hepatic involvement (> 50% of the liver involved), symptomatic lymphangitic metastases, or brain or leptomeningeal involvement

• Concomitant anticancer treatment with the following exceptions: (1) bisphosphonates for bone metastases, (2) a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued

• Grade 2 or more peripheral neuropathy

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with tipifarnib or other agents administered during the study.; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Montefiore Medical Center	Bronx	New York	United States	10467-2490

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Linda Vahdat, Montefiore Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00082810
• Other Study ID Numbers: NCI-2012-02982; 6205; N01CM62204
• First Posted: May 19, 2004
• Last Update Posted: Nov 1, 2018
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Breast Neoplasms; Fulvestrant; Tipifarnib

Study Results

Participant Flow

Recruitment Details	A total of 33 patients were enrolled from 3 institutions between March 2004 and August 2006. Two patients were ineligible; one had a performance status of three and elevated liver function tests that exceeded inclusion criteria, whereas the other received prior chemotherapy for metatstatic disease.

Arm/Group Title	Fulvestrant 250 mg + Tipifarnib 300 mg
Arm/Group Description	Patients receive fulvestrant 250 mg intramuscularly on day 1 and oral tipifarnib 300 mg twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
Period Title: Overall Study
STARTED	33
COMPLETED	2
NOT COMPLETED	31

Baseline Characteristics

Arm/Group Title	Fulvestrant 250 mg + Tipifarnib 300 mg
Arm/Group Description	Patients receive fulvestrant 250 mg intramuscularly on day 1 and oral tipifarnib 300 mg twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
Overall Participants	33
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61.0
Sex: Female, Male (Count of Participants)
Female	33 100%
Male	0 0%
Race/Ethnicity, Customized (participants) [Number]
Whites	14 42.4%
Black	3 9.1%
Hispanic	14 42.4%
Asian	2 6.1%

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate (CBR) (CR Rate, PR Rate, and SD)
Description	Number of participants met the definition of Clinical Benefit Rate.Tumor response was assessed every three cycles by CT using RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Per Response Evaluation Criteria in Solid Tumors (RECIST 1.0) for target lesions: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fulvestrant 250 mg + Tipifarnib 300 mg
Arm/Group Description	Patients receive fulvestrant 250 mg intramuscularly on day 1 and oral tipifarnib 300 mg twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
Measure Participants	31
Partial response	11 33.3%
Stable disease	5 15.2%
Complete response	0 0%

2. Secondary Outcome

Title	Time to Progression (TTP)
Description	TTP was estimated using the Kaplan-Meier method.
Time Frame	From randomization until progression of the disease, assessed up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fulvestrant 250 mg + Tipifarnib 300 mg
Arm/Group Description	Patients receive fulvestrant 250 mg intramuscularly on day 1 and oral tipifarnib 300 mg twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
Measure Participants	31
Median (95% Confidence Interval) [months]	7.2

3. Secondary Outcome

Title	Duration of Response
Description	DOR was defined for responders as the time from the onset of first response to disease progression and for non-responders as zero
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fulvestrant 250 mg + Tipifarnib 300 mg
Arm/Group Description	Patients receive fulvestrant 250 mg intramuscularly on day 1 and oral tipifarnib 300 mg twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
Measure Participants	16
Median (95% Confidence Interval) [months]	16

4. Secondary Outcome

Title	Toxicity as Assessed by NCI CTCAE Version 3.0
Description	Number of Participants with serious (grade 3) or life-threatening (grade 4) adverse events
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

All treated patients who received at least one dose of tipifarnib were included in the safety analysis. A total of 342 cycles of therapy were administered (median 7 cycles/patient range 1-36 cycles)

Arm/Group Title	Treatment (Tipifarnib, Fulvestrant)
Arm/Group Description	Patients receive fulvestrant intramuscularly on day 1 and oral tipifarnib twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity*. fulvestrant: Given intramuscularly tipifarnib: Given IV
Measure Participants	33
Count of Participants [Participants]	33 100%

5. Secondary Outcome

Title	Median Overall Survival
Description	The 95% confidence intervals will be used.
Time Frame	From randomization until death or censored at the date of last follow-up, assessed up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fulvestrant 250 mg + Tipifarnib 300 mg
Arm/Group Description	Patients receive fulvestrant 250 mg intramuscularly on day 1 and oral tipifarnib 300 mg twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
Measure Participants	31
Median (95% Confidence Interval) [months]	19.4

Adverse Events

Arm/Group Title	Fulvestrant 250 mg + Tipifarnib 300 mg
Arm/Group Description	Patients receive fulvestrant 250 mg intramuscularly on day 1 and oral tipifarnib 300 mg twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity
All Cause Mortality
	Fulvestrant 250 mg + Tipifarnib 300 mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Fulvestrant 250 mg + Tipifarnib 300 mg
	Affected / at Risk (%)	# Events
Total	20/33 (60.6%)
Blood and lymphatic system disorders
Neutropenia	4/33 (12.1%)
Anemia	2/33 (6.1%)
Cardiac disorders
Cardiac Ischemia	1/33 (3%)
Gastrointestinal disorders
Nausea	3/33 (9.1%)
Vomiting	2/33 (6.1%)
Diarrhea	1/33 (3%)
General disorders
Fatigue	1/33 (3%)
Infections and infestations
Infection	1/33 (3%)
Metabolism and nutrition disorders
Anorexia	1/33 (3%)
Hyperglycemia	1/33 (3%)
Hypocalcemia	2/33 (6.1%)
Hypokalemia	1/33 (3%)
Nervous system disorders
Ataxia	1/33 (3%)
Psychiatric disorders
Insomnia	1/33 (3%)
Anxiety	1/33 (3%)
Agitation	1/33 (3%)
Renal and urinary disorders
Creatinine	1/33 (3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/33 (3%)
Pneumonitis	1/33 (3%)
Skin and subcutaneous tissue disorders
Rash	1/33 (3%)
Other (Not Including Serious) Adverse Events
	Fulvestrant 250 mg + Tipifarnib 300 mg
	Affected / at Risk (%)	# Events
Total	15/33 (45.5%)
Blood and lymphatic system disorders
Anemia	8/33 (24.2%)
Gastrointestinal disorders
Nausea	12/33 (36.4%)
Vomiting	4/33 (12.1%)
Diarrhea	11/33 (33.3%)
General disorders
Fatigue	12/33 (36.4%)
Fever	3/33 (9.1%)
Infections and infestations
Infection	3/33 (9.1%)
Metabolism and nutrition disorders
Anorexia	6/33 (18.2%)
Hyperglycemia	5/33 (15.2%)
Nervous system disorders
Neuropathy	7/33 (21.2%)
Psychiatric disorders
Insomnia	4/33 (12.1%)
Anxiety	2/33 (6.1%)
Renal and urinary disorders
Creatinine	2/33 (6.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	4/33 (12.1%)
Skin and subcutaneous tissue disorders
Rash	2/33 (6.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.