A Study of Vismodegib (GDC-0449, Hedgehog Pathway Inhibitor) As Maintenance Therapy in Patients With Ovarian Cancer in a Second or Third Complete Remission

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00739661
• Collaborator: (none)
• Enrollment: 104
• Arms: 2
• Actual Duration (Months): 23

Study Details

Study Description

Brief Summary

The study was a Phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial of vismodegib (GDC-0449) in patients with ovarian cancer in a second or third complete remission. Patients were randomized in a 1:1 ratio to either vismodegib or placebo. Randomization was stratified based on whether their cancer was in a second or third complete remission.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Vismodegib 150 mg; Drug: Placebo to vismodegib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 104 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Vismodegib (GDC-0449) As Maintenance Therapy in Patients With Ovarian Cancer in a Second or Third Complete Remission
• Actual Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vismodegib 150 mg Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Drug: Vismodegib 150 mg; Vismodegib 150 mg was provided in hard gelatin capsules.; Other Names: GDC-0449
Placebo Comparator: Placebo to vismodegib Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Drug: Placebo to vismodegib; Placebo to vismodegib consisted of the excipients for vismodegib without the active molecule in hard gelatin capsules matching the active drug product in color and size.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks]

   PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Since patients were in remission at the start of the study, they had no evidence of the presence of tumors. Disease progression was defined as radiographic evidence of a tumor. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study.

Secondary Outcome Measures

1. Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression [From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks]

   Hedgehog antigen expression was measured with immunohistochemical methods in tumor tissue taken from each patient prior to enrollment in the study. The percentage of cells with (> 0%) and without (0%) Hedgehog antigen expression was measured microscopically. PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study.

2. Overall Survival [From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks]

   Overall survival was defined as the time from randomization until death by any cause.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologic diagnosis of epithelial ovarian carcinoma, primary peritoneal carcinoma, or fallopian tube carcinoma

• Must be in second or third complete remission, have received chemotherapy (platinum-based and/or non-platinum-based) for recurrent disease, and have achieved a complete remission after their most recent chemotherapy regimen. Complete remission is defined as no symptoms suggestive of persistent cancer, computed tomography (CT) scan of the chest/abdomen/pelvis without evidence of ovarian cancer within 4 weeks of randomization, and normal CA-125 (measured within 2 weeks of randomization) following completion of prior chemotherapy. The study investigator should confirm the status of disease remission by CT scan before patient enrollment. If patient has lymphadenopathy by CT scan and the investigator thinks that it is unlikely due to ovarian cancer, this patient is considered eligible. If indicated, a confirmatory biopsy should be performed.

• Patients must have completed their most recent cytotoxic chemotherapy regimen (platinum-based or non-platinum based) no less than 3 weeks and no more than 14 weeks prior to randomization.

• Archival tissue must be available and requested.

• Negative pregnancy test on Day 1 (first day the patient receives vismodegib or placebo).

• For women of childbearing potential: Use of two effective methods of contraception, including one barrier method.

Exclusion Criteria:

• Pregnancy or lactation.

• Patients whose ovarian cancer is in first remission.

• Patients must not have experienced more than two prior recurrences of disease.

• Concurrent non-protocol-specified anti-tumor therapy, either approved or unapproved (eg, chemotherapy, hormonal therapy, other targeted therapy, radiation therapy, surgery, herbal therapy). Hormonal replacement therapies for treatment of postmenopausal symptoms do not exclude patients from this study.

• Current, recent (within 4 weeks of Day 1), or planned participation in an experimental drug study while enrolled in this study.

• History of other malignancies within 3 years of Day 1, except for tumors with a negligible risk for metastasis or death, such as adequately treated basal cell carcinoma (BCC) or squamous-cell carcinoma of the skin; ductal carcinoma in situ of the breast; or carcinoma in situ of the cervix.

• Uncontrolled medical illnesses such as infection requiring intravenous (IV) antibiotics.

• Life expectancy < 12 weeks.

• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk from treatment complications.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Josina Reddy, M.D., Ph.D., Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00739661
• Other Study ID Numbers: SHH4489g
• First Posted: Aug 22, 2008
• Last Update Posted: Jun 8, 2017
• Last Verified: May 1, 2017

• Keywords provided by Genentech, Inc.: Systemic Hedgehog; Hedgehog Pathway Inhibitor
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial

Study Results

Participant Flow

Arm/Group Title	Vismodegib 150 mg	Placebo to Vismodegib
Arm/Group Description	Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.
Period Title: Overall Study
STARTED	52	52
COMPLETED	6	10
NOT COMPLETED	46	42

Baseline Characteristics

Arm/Group Title	Vismodegib 150 mg	Placebo to Vismodegib	Total
Arm/Group Description	Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Total of all reporting groups
Overall Participants	52	52	104
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.3 (10.2)	58.6 (8.9)	57.9 (9.6)
Sex: Female, Male (Count of Participants)
Female	52 100%	52 100%	104 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Since patients were in remission at the start of the study, they had no evidence of the presence of tumors. Disease progression was defined as radiographic evidence of a tumor. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study.
Time Frame	From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat patient population: All randomized patients.

Arm/Group Title	Vismodegib 150 mg	Placebo to Vismodegib
Arm/Group Description	Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.
Measure Participants	52	52
Median (95% Confidence Interval) [Months]	7.5	5.8

2. Secondary Outcome

Title	Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression
Description	Hedgehog antigen expression was measured with immunohistochemical methods in tumor tissue taken from each patient prior to enrollment in the study. The percentage of cells with (> 0%) and without (0%) Hedgehog antigen expression was measured microscopically. PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study.
Time Frame	From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat patient population: All randomized patients. Tissue for evaluation was only available for 29 patients in the vismodegib group and 28 patients in the placebo group.

Arm/Group Title	Vismodegib 150 mg	Placebo to Vismodegib
Arm/Group Description	Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.
Measure Participants	29	28
0% of cells with hedgehog punctate stain	7.00 (3.48)	5.32
> 0% of cells with Hedgehog punctate stain	9.13	7.36

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from randomization until death by any cause.
Time Frame	From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat patient population: All randomized patients.

Arm/Group Title	Vismodegib 150 mg	Placebo to Vismodegib
Arm/Group Description	Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.	Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.
Measure Participants	52	52
Mean (Standard Deviation) [Months]	NA (NA)	NA (NA)

Adverse Events

Time Frame	Adverse events and serious adverse events were recorded starting at randomization until 45 days after the last dose of treatment or after the initiation of new anti-tumor therapy, whichever was earlier, up to 100 weeks.
Adverse Event Reporting Description	Adverse events were reported for the safety-evaluable population, which was defined as all patients who received at least one dose of study treatment.
Arm/Group Title	Vismodegib 150 mg		Placebo to Vismodegib
Arm/Group Description	Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.		Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study.
All Cause Mortality
	Vismodegib 150 mg		Placebo to Vismodegib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Vismodegib 150 mg		Placebo to Vismodegib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/52 (11.5%)		3/52 (5.8%)
Cardiac disorders
Cardiac Failure Congestive	1/52 (1.9%)		0/52 (0%)
Gastrointestinal disorders
Abdominal Pain	1/52 (1.9%)		0/52 (0%)
Small Intestinal Obstruction	0/52 (0%)		1/52 (1.9%)
General disorders
Chest Pain	1/52 (1.9%)		0/52 (0%)
Infections and infestations
Device Related Infection	0/52 (0%)		1/52 (1.9%)
Urinary Tract Infection	0/52 (0%)		1/52 (1.9%)
Investigations
Hepatic Enzyme Increased	1/52 (1.9%)		0/52 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung Adenocarcinoma	1/52 (1.9%)		0/52 (0%)
Renal and urinary disorders
Renal Colic	1/52 (1.9%)		0/52 (0%)
Respiratory, thoracic and mediastinal disorders
Emphysema	1/52 (1.9%)		0/52 (0%)
Pneumothorax	1/52 (1.9%)		0/52 (0%)
Other (Not Including Serious) Adverse Events
	Vismodegib 150 mg		Placebo to Vismodegib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/52 (98.1%)		44/52 (84.6%)
Gastrointestinal disorders
Nausea	17/52 (32.7%)		9/52 (17.3%)
Abdominal Pain	10/52 (19.2%)		7/52 (13.5%)
Constipation	12/52 (23.1%)		5/52 (9.6%)
Diarrhoea	6/52 (11.5%)		8/52 (15.4%)
Vomiting	8/52 (15.4%)		5/52 (9.6%)
Abdominal Pain Upper	9/52 (17.3%)		3/52 (5.8%)
Abdominal Discomfort	2/52 (3.8%)		4/52 (7.7%)
Abdominal Distension	2/52 (3.8%)		4/52 (7.7%)
Dry Mouth	5/52 (9.6%)		1/52 (1.9%)
Flatulence	2/52 (3.8%)		4/52 (7.7%)
Dyspepsia	3/52 (5.8%)		2/52 (3.8%)
Abdominal Pain Lower	3/52 (5.8%)		1/52 (1.9%)
General disorders
Fatigue	14/52 (26.9%)		15/52 (28.8%)
Asthenia	5/52 (9.6%)		3/52 (5.8%)
Infections and infestations
Influenza	4/52 (7.7%)		3/52 (5.8%)
Urinary Tract Infection	3/52 (5.8%)		0/52 (0%)
Investigations
Weight Decreased	6/52 (11.5%)		1/52 (1.9%)
Metabolism and nutrition disorders
Decreased Appetite	10/52 (19.2%)		1/52 (1.9%)
Hypomagnesaemia	3/52 (5.8%)		1/52 (1.9%)
Musculoskeletal and connective tissue disorders
Muscle Spasms	35/52 (67.3%)		1/52 (1.9%)
Arthralgia	8/52 (15.4%)		8/52 (15.4%)
Back Pain	6/52 (11.5%)		4/52 (7.7%)
Musculoskeletal Pain	5/52 (9.6%)		3/52 (5.8%)
Pain In Extremity	4/52 (7.7%)		2/52 (3.8%)
Myalgia	3/52 (5.8%)		2/52 (3.8%)
Nervous system disorders
Dysgeusia	35/52 (67.3%)		9/52 (17.3%)
Headache	5/52 (9.6%)		6/52 (11.5%)
Dizziness	4/52 (7.7%)		5/52 (9.6%)
Neuropathy Peripheral	2/52 (3.8%)		4/52 (7.7%)
Paraesthesia	3/52 (5.8%)		3/52 (5.8%)
Ageusia	4/52 (7.7%)		1/52 (1.9%)
Psychiatric disorders
Insomnia	3/52 (5.8%)		3/52 (5.8%)
Anxiety	3/52 (5.8%)		2/52 (3.8%)
Depression	3/52 (5.8%)		0/52 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	5/52 (9.6%)		5/52 (9.6%)
Oropharyngeal Pain	2/52 (3.8%)		3/52 (5.8%)
Skin and subcutaneous tissue disorders
Alopecia	28/52 (53.8%)		4/52 (7.7%)
Rash	6/52 (11.5%)		2/52 (3.8%)
Pruritus	4/52 (7.7%)		3/52 (5.8%)
Nail Disorder	0/52 (0%)		3/52 (5.8%)
Vascular disorders
Hypertension	2/52 (3.8%)		3/52 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.