Vismodegib in Treating Patients With Advanced Chondrosarcomas

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01267955
• Collaborator: (none)
• Enrollment: 45
• Locations: 6
• Arm: 1
• Patients Per Site: 7.5

Study Details

Study Description

Brief Summary

This phase II trial studies how well vismodegib works in treating patients with chondrosarcomas that have spread to other places in the body and usually cannot be cured or controlled with treatment. Drugs used in chemotherapy, such as vismodegib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Chondrosarcoma; Dedifferentiated Chondrosarcoma; Locally Advanced Chondrosarcoma; Mesenchymal Chondrosarcoma; Metastatic Chondrosarcoma; Primary Central Chondrosarcoma; Unresectable Primary Central Chondrosarcoma	Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Drug: Vismodegib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the antitumor activity of GDC-0449 (vismodegib) in terms of 6-month clinical benefit rate (complete response, partial response, and stable disease, as per the revised Response Evaluation Criteria in Solid Tumors [RECIST] criteria 2009).

SECONDARY OBJECTIVES:

1. Best overall response (as per the revised RECIST criteria 2009). II. 1- and 2-year progression-free survival. III. 1- and 2-year overall survival. IV. GDC-0449 safety. V. Pharmacogenomics analysis of predictive markers of treatment outcome.

OUTLINE:

Patients receive vismodegib orally (PO) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of GDC-0449 in Patients With Advanced Chondrosarcomas
• Actual Study Start Date: Dec 21, 2010
• Actual Primary Completion Date: Jun 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (vismodegib) Patients receive vismodegib PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacogenomic Study; Correlative studies; Other Names: PHARMACOGENOMIC ; Drug: Vismodegib; Given PO; Other Names: Erivedge GDC-0449 Hedgehog Antagonist GDC-0449

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate (CBR) Based on Centralized Imaging Review as Per RECIST 1.1 [At 6 months after inclusion]

   CBR was defined as the percentage of participants with complete or partial responses (CR, PR) or stable disease (SD) per RECIST 1.1. CR was defined as disappearance of all non-nodal target lesions. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Analysis of response was performed based on radiological centralized review. A 2-stage optimal Simon's design with 37 participants (first stage: 17 participants) was used. If 3 or less non-progressions (CR + PR + SD) at 6 months were observed during stage 1 (out of 17 participants), the trial would stopped early. Otherwise, 20 additional patients would be accrued for stage 2. If 11 or more non-progressions (out of 37 participants) were observed at the end of recruitment, further investigation of this therapy would be warranted.

Secondary Outcome Measures

1. Progression-free Survival [Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years]

   Will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.

2. Overall Survival Per Response Evaluation Criteria in Solid Tumors Criteria 2009 [Time from start of treatment to the time of death, assessed up to 3 years]

   Overall survival will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.

3. Duration of Response [From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years]

   Will be described in responding subjects using descriptive statistics (median, extreme values, etc.).

4. Mutational Status of Patched 1 and Smoothened [Baseline]

   The 6-months clinical benefit rate will be correlated with the mutational status of patched and smoothened in order to identify predictive factors of clinical benefit from vismodegib.

5. Expression Pattern of Hedgehog Signaling Molecules by Using Quantitative Reverse Transcription-polymerase Chain Reaction and Immunohistochemistry [Baseline]

   The 6-months clinical benefit rate will be correlated with the expression score of hedgehog signaling molecules in order to identify predictive factors of clinical benefit from vismodegib.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically confirmed diagnosis of chondrosarcoma (conventional, mesenchymal, dedifferentiated or clear cell subtypes)

• Patients must have measurable disease (outside any previously irradiated field) defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with spiral computed tomography (CT) scan

• No more than three prior lines of chemotherapy for advanced disease (including no more than 450 mg/m^2 doxorubicin); at least three weeks since last chemotherapy (six weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy

• Life expectancy of greater than 3 months

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal

• Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• Metastatic or unresectable locally advanced disease

• Documented disease progression (as per RECIST) before study entry

• Women of child-bearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 24 months post-treatment for female patients and for 2 months for male patients; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 7 days prior to initiation of GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks while on study within the 24-hour period prior to the administration of GDC-0449; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing GDC-0449, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of GDC-0449

• Women of childbearing potential are defined as follows:

• Patients with regular menses

• Patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding

• Women who have had a tubal ligation

• Women are considered not to be of childbearing potential for the following reasons:

• The patient has undergone hysterectomy and/or bilateral oophorectomy

• The patient is post-menopausal defined by amenorrhea for at least 1 year in a woman > 50 years old

• The patient has permanent premature ovarian failure confirmed by specialist gynecologist

• Ability to understand and the willingness to sign a written informed consent document

• In accordance with French Regulatory Authorities: Patients with French Social Security in compliance with the French law relating to biomedical research (Huriet Law 88-1138 and related decrees)

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier

• Patients may not be receiving any other investigational agents

• Patients with known brain metastases should be excluded from this clinical trial

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or other agents used in the study

• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow capsules

• Patients with clinically important history of liver disease, including viral or other hepatitis, or cirrhosis are ineligible

• Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation, are excluded from this study

• Tumor tissue sample not available for pathological review and/or correlative studies

• 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

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with GDC-0449; these potential risks may also apply to other agents used in this study

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institut Bergonie Cancer Center	Bordeaux		France	33076
2	Centre Oscar Lambert	Lille		France	59020
3	Centre Leon Berard	Lyon		France	69373
4	Hopital De La Timone	Marseille		France	13385
5	Institut Curie Paris	Paris		France	75005
6	Gustave Roussy	Villejuif		France	94805

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Antoine Italiano, Institut Bergonie Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 17, 2017

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01267955
• Other Study ID Numbers: NCI-2011-02564; NCI-2011-02564; CDR0000691728; IB-CHONDROG; CHONDROG; 8408; 8408
• First Posted: Dec 29, 2010
• Last Update Posted: Jul 28, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Chondrosarcoma; Chondrosarcoma, Mesenchymal; Chondrosarcoma, Clear Cell

Study Results

Participant Flow

Arm/Group Title	Treatment (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Vismodegib: Given PO This is a single-arm phase 2 trial, based on a two-stage Simon's optimal design. Assuming 20% (H0: null hypothesis) and 40% (H1: alternative hypothesis) six-month CBR, 10% type I error rate and 90% power, 37 eligible and assessable patients were necessary (17 in the first stage and 20 in the second stage). At the second stage/final stage, GDC-0449 would be considered promising if at least eleven patients were progression-free at 6 months.
Period Title: Stage 1 (6 Months)
STARTED	20
COMPLETED	17
NOT COMPLETED	3
Period Title: Stage 1 (6 Months)
STARTED	45
COMPLETED	39
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Treatment (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Vismodegib: Given PO
Overall Participants	45
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58.0
Sex: Female, Male (Count of Participants)
Female	14 31.1%
Male	31 68.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
Asian
Native Hawaiian or Other Pacific Islander
Black or African American
White
More than one race
Unknown or Not Reported
Region of Enrollment (participants) [Number]
France	45 100%
ECOG Performance status (Count of Participants)
0	20 44.4%
1	20 44.4%
2	5 11.1%
Weight (kilogram) [Median (Full Range) ]
Median (Full Range) [kilogram]	76.5
Height (millimetres) [Median (Full Range) ]
Median (Full Range) [millimetres]	173.0
Histological subtype (Count of Participants)
Conventional chondrosarcoma	39 86.7%
Dedifferentiated chondrosarcoma	5 11.1%
Clear cell chondrosarcoma	1 2.2%
Mesenchymal chondrosarcoma	0 0%
Stage of the disease (Count of Participants)
Locally advanced	13 28.9%
Metastatic	32 71.1%
Prior lines of chemotherapy (Count of Participants)
0	25 55.6%
1	12 26.7%
2	3 6.7%
>2	5 11.1%

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate (CBR) Based on Centralized Imaging Review as Per RECIST 1.1
Description	CBR was defined as the percentage of participants with complete or partial responses (CR, PR) or stable disease (SD) per RECIST 1.1. CR was defined as disappearance of all non-nodal target lesions. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Analysis of response was performed based on radiological centralized review. A 2-stage optimal Simon's design with 37 participants (first stage: 17 participants) was used. If 3 or less non-progressions (CR + PR + SD) at 6 months were observed during stage 1 (out of 17 participants), the trial would stopped early. Otherwise, 20 additional patients would be accrued for stage 2. If 11 or more non-progressions (out of 37 participants) were observed at the end of recruitment, further investigation of this therapy would be warranted.
Time Frame	At 6 months after inclusion

Outcome Measure Data

Analysis Population Description

Eligible participants with at least one complete or two incomplete cycles of treatment and for whom at least one disease measurement has been recorded not less than 8 weeks after treatment onset.

Arm/Group Title	Treatment (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Vismodegib: Given PO
Measure Participants	39
First stage	23.5 52.2%
Second stage (Overall)	25.6 56.9%

2. Secondary Outcome

Title	Progression-free Survival
Description	Will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.
Time Frame	Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Overall Survival Per Response Evaluation Criteria in Solid Tumors Criteria 2009
Description	Overall survival will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.
Time Frame	Time from start of treatment to the time of death, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Duration of Response
Description	Will be described in responding subjects using descriptive statistics (median, extreme values, etc.).
Time Frame	From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Mutational Status of Patched 1 and Smoothened
Description	The 6-months clinical benefit rate will be correlated with the mutational status of patched and smoothened in order to identify predictive factors of clinical benefit from vismodegib.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Expression Pattern of Hedgehog Signaling Molecules by Using Quantitative Reverse Transcription-polymerase Chain Reaction and Immunohistochemistry
Description	The 6-months clinical benefit rate will be correlated with the expression score of hedgehog signaling molecules in order to identify predictive factors of clinical benefit from vismodegib.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	14 months of treatment. At the time of primary analysis, 8 were still on treatment and 37 patients discontinued treatment.
Adverse Event Reporting Description	Adverse event are reported for all treated patients who received at least one administration of treatment.
Arm/Group Title	Treatment (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Pharmacogenomic Study: Correlative studies Vismodegib: Given PO
All Cause Mortality
	Treatment (Vismodegib)
	Affected / at Risk (%)	# Events
Total	23/45 (51.1%)
Serious Adverse Events
	Treatment (Vismodegib)
	Affected / at Risk (%)	# Events
Total	22/45 (48.9%)
Blood and lymphatic system disorders
ANEMIA	2/45 (4.4%)	2
Gastrointestinal disorders
ABDOMINAL PAIN	1/45 (2.2%)	1
CONSTIPATION	1/45 (2.2%)	1
General disorders
General disorders and administration site conditions - Other, specify	2/45 (4.4%)	2
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	1/45 (2.2%)	1
Infections and infestations
Sepsis	3/45 (6.7%)	3
Urinary tract infection	1/45 (2.2%)	1
Injury, poisoning and procedural complications
Fracture	1/45 (2.2%)	1
Investigations
GGT increased	1/45 (2.2%)	1
Alanine aminotransferase increased	1/45 (2.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	2/45 (4.4%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	5/45 (11.1%)	5
Nervous system disorders
Cognitive disturbance	1/45 (2.2%)	1
Transient ischemic attacks	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	3/45 (6.7%)	3
Dyspnea	1/45 (2.2%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	2/45 (4.4%)	2
Vascular disorders
Thromboembolic event	2/45 (4.4%)	2
Phlebitis	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Vismodegib)
	Affected / at Risk (%)	# Events
Total	45/45 (100%)
Blood and lymphatic system disorders
ANEMIA	9/45 (20%)	15
Blood and lymphatic system disorders - Other, specify	3/45 (6.7%)	4
Gastrointestinal disorders
Abdominal pain	9/45 (20%)	9
Constipation	8/45 (17.8%)	10
Diarrhea	13/45 (28.9%)	19
Dry mouth	3/45 (6.7%)	3
Gastroesophageal reflux disease	3/45 (6.7%)	3
Mucositis oral	3/45 (6.7%)	3
Nausea	17/45 (37.8%)	20
Stomach pain	3/45 (6.7%)	5
Vomiting	7/45 (15.6%)	7
General disorders
Chills	3/45 (6.7%)	4
Edema limbs	3/45 (6.7%)	3
Fatigue	24/45 (53.3%)	28
Fever	8/45 (17.8%)	13
General disorders and administration site conditions - Other, specify	3/45 (6.7%)	3
Infections and infestations
Bronchial infection	4/45 (8.9%)	4
Sepsis	3/45 (6.7%)	3
Urinary tract infection	3/45 (6.7%)	4
Investigations
Alanine aminotransferase increased	7/45 (15.6%)	9
Alkaline phosphatase increased	5/45 (11.1%)	5
Aspartate aminotransferase increased	5/45 (11.1%)	5
GGT increased	5/45 (11.1%)	6
Lymphocyte count decreased	4/45 (8.9%)	5
Weight loss	12/45 (26.7%)	12
Investigations - Other, specify	5/45 (11.1%)	8
Metabolism and nutrition disorders
Anorexia	12/45 (26.7%)	15
Hypercalcemia	7/45 (15.6%)	11
Hyperkalemia	5/45 (11.1%)	6
Hypoalbuminemia	6/45 (13.3%)	9
Hypokalemia	3/45 (6.7%)	3
Hypomagnesemia	4/45 (8.9%)	6
Hyponatremia	3/45 (6.7%)	6
Musculoskeletal and connective tissue disorders
Back pain	3/45 (6.7%)	3
Myalgia	23/45 (51.1%)	27
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	8/45 (17.8%)	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	4/45 (8.9%)	4
Nervous system disorders
Dizziness	3/45 (6.7%)	3
Dysesthesia	3/45 (6.7%)	3
Dysgeusia	29/45 (64.4%)	30
Headache	6/45 (13.3%)	8
Paresthesia	3/45 (6.7%)	4
Psychiatric disorders
Anxiety	3/45 (6.7%)	3
Confusion	4/45 (8.9%)	4
Insomnia	4/45 (8.9%)	4
Renal and urinary disorders
Urinary frequency	3/45 (6.7%)	21
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	3/45 (6.7%)	3
Cough	4/45 (8.9%)	4
Dyspnea	7/45 (15.6%)	7
Skin and subcutaneous tissue disorders
Alopecia	18/45 (40%)	18
Rash acneiform	3/45 (6.7%)	3
Skin and subcutaneous tissue disorders - Other, specify	3/45 (6.7%)	3
Vascular disorders
Lymphedema	3/45 (6.7%)	4
Thromboembolic event	4/45 (8.9%)	4

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.