Vismodegib and Gemcitabine Hydrochloride in Treating Patients With Advanced Pancreatic Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01195415
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 52.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This pilot clinical trial studies vismodegib and gemcitabine hydrochloride in treating patients with advanced pancreatic cancer. Vismodegib may stop the growth of pancreatic cancer by blocking blow flow to the tumor. Gemcitabine hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib and gemcitabine hydrochloride may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Pancreatic Carcinoma; Stage IV Pancreatic Cancer	Drug: Gemcitabine Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Vismodegib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To obtain tumor biopsies before and after therapy with GDC-0449 (vismodegib) to evaluate the effect of inhibition of hedgehog signaling on pancreatic cancer stem cells by: evaluating the tumor for number and percentage of pancreatic cancer stem cells before and after treatment with GDC-0449.

SECONDARY OBJECTIVES:

1. To assess progression free survival (PFS) at 3 months following treatment with GDC-0449 and gemcitabine (gemcitabine hydrochloride).

2. To assess response rate to treatment and overall survival in patients with advanced pancreas cancer treated with GDC-0449 alone and in combination with gemcitabine.

3. To evaluate the toxicity of GDC-0449 alone and in combination with gemcitabine.

OUTLINE:

Patients receive vismodegib orally (PO) once daily (QD) on days 1-28 and gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Cancer Stem Cells and Inhibition of Hedgehog Pathway Signaling in Advanced Pancreas Cancer: A Pilot Study of GDC-0449 in Combination With Gemcitabine
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Oct 10, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (vismodegib, gemcitabine hydrochloride) Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Gemcitabine Hydrochloride; Given IV; Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride Gemzar LY-188011 LY188011 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Vismodegib; Given PO; Other Names: Erivedge GDC-0449 Hedgehog Antagonist GDC-0449

Outcome Measures

Primary Outcome Measures

1. Median Percent at Baseline and 3 Weeks in CD44+/ CD24+/ ESA+ Cells From Needle Biopsy Calculated Using FACS [3 weeks]

   The median percentage of CD44+CD24+ESA+ cells from needle biopsy were calculated at baseline and at 3 weeks using FACS. The difference between the two time points was calculated.

Secondary Outcome Measures

1. The Number of Participants With an Objective Best Response (CR + PR) [Up to 4 weeks]

   The number of participants with either a complete response (CR) or a partial response (PR) will be calculated. A CR is defined as the disappearance of all target lesions. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions.

2. Median Progression Free Survival [Up to 24 months]

   Median progression free survival was calculated for all treated patients. Assessed using the Kaplan-Meier method. The 95% confidence interval for this estimate will be computed using the Greenwood's formula.

3. Percentage of Treated Patients Experiencing Grade 3+ Toxicity Per National Cancer Institute Common Toxicity Criteria (CTC) Version 3.0 [Up to 4 weeks]

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 or cytologically confirmed pancreas cancer

• Patients must have metastatic disease or recurrent disease following surgical therapy

• 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) >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan

• Patients must have disease accessible for core needle biopsy both prior to initiation of therapy and on day 21 (+ or - 1 day) of GDC-0449 treatment

• No previous systemic therapy for metastatic pancreas cancer is permitted; prior neoadjuvant or adjuvant therapy with chemotherapy and/or radiation is allowed provided that the last day of therapy was at least 6 months prior to registration

• Life expectancy of greater than 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 2.0 mg/dl

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal; < 5 x if liver involved in tumor

• Creatinine < 2.0 mg/dl

• The effects of GDC-0449 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because hedgehog (Hh) signal pathway inhibitors as well as gemcitabine are known to be teratogenic, 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 12 months post-treatment; for appropriate methods of contraception considered acceptable; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately;

• Pregnancy testing: omen of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL beta-human chorionic gonadotropin [bHCG]) within 10-14 days and within 24 hours prior to the first dose of GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular 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

• Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450) may be enrolled with caution; GDC-0449 is a substrate of CYP3A4; however, the in vitro metabolic conversion of GDC-0449 is low; effects of cytochrome (CYP) inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wart, and troglitazone) on clinical concentrations of GDC-0449 are unknown; likewise, the effects of strong inhibitors of CYP3A4 (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, and telithromycin) on GDC-0449 clinical concentrations are unknown, and caution should be exercised when dosing GDC-0449 concurrently with inhibitors of CYP3A4; in addition, GDC-0449 inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro at concentrations that may be clinically relevant; therefore, caution should be exercised when dosing GDC-0449 concurrently with medications that are substrates of CYP2C8, CYP2C9, and CYP2C19 and have narrow therapeutic windows

• Ability to understand and willingness to provide written informed consent

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 6 months prior to entering the study or those who have not recovered from adverse events due to agents administered more than 6 months earlier

• Patients may not be receiving any other investigational agents

• Patients with known brain metastases

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

• Patients on anticoagulation with Coumadin are ineligible; however anticoagulation with enoxaparin is acceptable for study entry

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

• Patients with clinically active liver disease, including active viral or other hepatitis or cirrhosis, are ineligible

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

• Patients with > grade 1 hyponatremia or hypocalcemia are excluded from this study

• 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 because GDC-0449 is a Hh pathway inhibiting agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with GDC-0449, 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 because of the potential for pharmacokinetic interactions with GDC-0449; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mark Zalupski, University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01195415
• Other Study ID Numbers: NCI-2011-03746; NCI-2011-03746; UMCC 2010-003; 8417; P30CA046592; NCT01143415
• First Posted: Sep 6, 2010
• Last Update Posted: Aug 7, 2017
• Last Verified: Aug 1, 2017

• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine

Study Results

Participant Flow

Arm/Group Title	Treatment (Vismodegib, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	25
COMPLETED	23
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Vismodegib, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	10 40%
Male	15 60%

Outcome Measures

1. Primary Outcome

Title	Median Percent at Baseline and 3 Weeks in CD44+/ CD24+/ ESA+ Cells From Needle Biopsy Calculated Using FACS
Description	The median percentage of CD44+CD24+ESA+ cells from needle biopsy were calculated at baseline and at 3 weeks using FACS. The difference between the two time points was calculated.
Time Frame	3 weeks

Outcome Measure Data

Analysis Population Description

Of the 25 patients enrolled, only 22 were evaluable for the primary endpoint.

Arm/Group Title	Treatment (Vismodegib, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	22
Baseline Median % of CD44+/CD24+/ESA+ CSCs	4.79
3 Weeks Post Tx Median % of CD44+/CD24+/ESA+ CSCs	3.09

2. Secondary Outcome

Title	The Number of Participants With an Objective Best Response (CR + PR)
Description	The number of participants with either a complete response (CR) or a partial response (PR) will be calculated. A CR is defined as the disappearance of all target lesions. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

All treated patients were evaluable.

Arm/Group Title	Treatment (Vismodegib, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	25
Number [participants]	5 20%

3. Secondary Outcome

Title	Median Progression Free Survival
Description	Median progression free survival was calculated for all treated patients. Assessed using the Kaplan-Meier method. The 95% confidence interval for this estimate will be computed using the Greenwood's formula.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vismodegib, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	25
Median (95% Confidence Interval) [months]	2.8

4. Secondary Outcome

Title	Percentage of Treated Patients Experiencing Grade 3+ Toxicity Per National Cancer Institute Common Toxicity Criteria (CTC) Version 3.0
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vismodegib, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	25
Number [percentage of patients]	56

Adverse Events

Arm/Group Title	Treatment (Vismodegib, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Vismodegib, Gemcitabine Hydrochloride)
	Affected / at Risk (%)	# Events
Total	1/25 (4%)
Serious Adverse Events
	Treatment (Vismodegib, Gemcitabine Hydrochloride)
	Affected / at Risk (%)	# Events
Total	16/25 (64%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/25 (4%)	1
Gastrointestinal disorders
Abdominal pain	2/25 (8%)	2
Duodenal stenosis	1/25 (4%)	1
Small intestinal obstruction	1/25 (4%)	1
Upper gastrointestinal hemorrhage	1/25 (4%)	1
Vomiting	1/25 (4%)	1
General disorders
Fatigue	1/25 (4%)	1
Fever	1/25 (4%)	1
General disorders and administration site conditions - Other	2/25 (8%)	2
Multi-organ failure	1/25 (4%)	1
Death	1/25 (4%)	1
Hepatobiliary disorders
Hepatobiliary disorders - Other	1/25 (4%)	1
Investigations
Aspartate aminotransferase increased	1/25 (4%)	1
Blood bilirubin increased	1/25 (4%)	1
Metabolism and nutrition disorders
Anorexia	1/25 (4%)	1
Dehydration	3/25 (12%)	3
Hypercalcemia	1/25 (4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	2/25 (8%)	2
Nervous system disorders
Cognitive disturbance	1/25 (4%)	1
Renal and urinary disorders
Urinary tract obstruction	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/25 (4%)	1
Pleural effusion	1/25 (4%)	1
Surgical and medical procedures
Surgical and medical procedures - Other	1/25 (4%)	1
Vascular disorders
Hypotension	2/25 (8%)	2
Superior vena cava syndrome	1/25 (4%)	1
Thromboembolic event	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Vismodegib, Gemcitabine Hydrochloride)
	Affected / at Risk (%)	# Events
Total	25/25 (100%)
Blood and lymphatic system disorders
Anemia	17/25 (68%)	29
Cardiac disorders
Chest pain - cardiac	2/25 (8%)	2
Ear and labyrinth disorders
Tinnitus	3/25 (12%)	3
Vertigo	2/25 (8%)	2
Eye disorders
Photophobia	2/25 (8%)	2
Gastrointestinal disorders
Abdominal distension	4/25 (16%)	5
Abdominal pain	13/25 (52%)	19
Ascites	3/25 (12%)	4
Constipation	7/25 (28%)	9
Diarrhea	8/25 (32%)	8
Dry mouth	3/25 (12%)	3
Dyspepsia	3/25 (12%)	3
Flatulence	2/25 (8%)	2
Gastroesophageal reflux disease	2/25 (8%)	2
Gastroparesis	2/25 (8%)	2
Nausea	14/25 (56%)	16
Vomiting	13/25 (52%)	15
General disorders
Chills	3/25 (12%)	3
Edema limbs	7/25 (28%)	8
Fatigue	18/25 (72%)	28
Fever	10/25 (40%)	14
General disorders and administration site conditions - Other	2/25 (8%)	2
Non-cardiac chest pain	2/25 (8%)	2
Hepatobiliary disorders
Hepatobiliary disorders - Other	2/25 (8%)	2
Infections and infestations
Papulopustular rash	3/25 (12%)	3
Investigations
Alanine aminotransferase increased	17/25 (68%)	22
Aspartate aminotransferase increased	18/25 (72%)	24
Blood bilirubin increased	8/25 (32%)	11
CD4 lymphocytes decreased	3/25 (12%)	6
Creatinine increased	3/25 (12%)	3
Lipase increased	2/25 (8%)	2
Lymphocyte count decreased	11/25 (44%)	12
Neutrophil count decreased	8/25 (32%)	9
Platelet count decreased	13/25 (52%)	18
Weight gain	6/25 (24%)	6
Weight loss	10/25 (40%)	12
White blood cell decreased	10/25 (40%)	13
Metabolism and nutrition disorders
Anorexia	19/25 (76%)	24
Dehydration	5/25 (20%)	5
Hypercalcemia	4/25 (16%)	4
Hyperglycemia	18/25 (72%)	22
Hyperkalemia	9/25 (36%)	11
Hypoalbuminemia	11/25 (44%)	16
Hypocalcemia	13/25 (52%)	17
Hypoglycemia	2/25 (8%)	2
Hyponatremia	19/25 (76%)	23
Hypophosphatemia	11/25 (44%)	14
Musculoskeletal and connective tissue disorders
Arthralgia	4/25 (16%)	4
Arthritis	3/25 (12%)	3
Back pain	5/25 (20%)	6
Myalgia	7/25 (28%)	10
Pain in extremity	3/25 (12%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	2/25 (8%)	2
Nervous system disorders
Dizziness	4/25 (16%)	4
Dysgeusia	14/25 (56%)	16
Headache	6/25 (24%)	6
Somnolence	3/25 (12%)	3
Psychiatric disorders
Anxiety	7/25 (28%)	7
Confusion	3/25 (12%)	4
Depression	5/25 (20%)	5
Insomnia	3/25 (12%)	3
Renal and urinary disorders
Renal and urinary disorders - Other	2/25 (8%)	2
Urinary frequency	2/25 (8%)	2
Respiratory, thoracic and mediastinal disorders
Cough	6/25 (24%)	7
Dyspnea	7/25 (28%)	8
Hiccups	2/25 (8%)	2
Productive cough	5/25 (20%)	5
Skin and subcutaneous tissue disorders
Alopecia	8/25 (32%)	10
Pruritus	3/25 (12%)	3
Rash maculo-papular	2/25 (8%)	2
Vascular disorders
Hypertension	2/25 (8%)	2
Hypotension	7/25 (28%)	8

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.