A Trial of Cabozantinib (XL184) and Gemcitabine in Advanced Pancreatic Cancer

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01663272
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 56
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Gemcitabine is considered one of the standard drugs for advanced pancreatic cancer and is approved by the FDA to treat it. Cabozantinib is a new drug that has demonstrated effectiveness against pancreatic cancer in laboratory experiments, especially when given with gemcitabine. Initial studies with cabozantinib in pancreatic cancer have shown some activity against the disease. The purpose of this study is to determine the safest and highest dose of cabozantinib that can be given together with standard doses of gemcitabine in patients with pancreatic cancer. This study will determine the safety and tolerability of this two drug combination.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Drug: CABOZANTINIB; Drug: gemcitabine	Phase 1

Detailed Description

Preclinical work at the University of Michigan has demonstrated that inhibition of c-Met with cabozantinib prevented the development of metastatic disease in an intra-cardiac injection model in NOD/SCID mice. Additionally, the combination of cabozantinib and gemcitabine demonstrated improved tumor control compared to either agent alone in a relevant orthotopic implantation mouse model.

Combining gemcitabine with the c-Met inhibitor cabozantinib in advanced pancreatic cancer is a novel strategy that takes advantage of an established cytotoxic agent with one that targets a pathway known to be important for the growth, dissemination, and resistance of this disease.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial of Cabozantinib (XL184) and Gemcitabine in Advanced Pancreatic Cancer
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: cabozantinib with gemcitabine The Study Treatment Period will consist of continued treatment during which time patients will receive cabozantinib and gemcitabine until either disease progression or the occurrence of unacceptable drug-related toxicity	Drug: CABOZANTINIB; Daily oral cabozantinib administered days -7 until disease progression, intolerable adverse event(s) or patient choice.; Other Names: XL184 ; Drug: gemcitabine; Gemcitabine administered intravenously on days 1, 8, and 15 every 28 days.; Other Names: Gemzar

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose [5 weeks]

   The MTD is defined at the highest dose level at which ≤25% of patients experience a dose-limiting toxicity (DLT).

Secondary Outcome Measures

1. Median Progression-free Survival (PFS) [day-7 of cycle 1 until 30 days post treatment]

   Progression-free survival (PFS, a secondary endpoint) will be calculated from day-7 of cycle 1 of study treatment, until documented disease progression or death. Patients removed from treatment for progression or other reasons will be followed for 30 days after their last dose.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. pathologically confirmed pancreatic carcinoma.

2. locally advanced unresectable disease, metastatic disease, or recurrent disease following surgical therapy.

3. ≥ 18 years old.

4. Life expectancy of greater than 12 weeks.

5. ECOG performance status ≤1 (Karnofsky ≥70%) (See Appendix A).

6. adequate organ and marrow function as follows:

7. capable of understanding and complying with the protocol requirements and has signed the informed consent document.

8. use medically accepted barrier methods of contraception

9. women of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

1. neuroendocrine tumors of the pancreas.

2. more than 1 prior systemic treatment regimen for pancreatic cancer. may have received prior neoadjuvant or adjuvant therapy, including gemcitabine, provided 6 months have elapsed from completion of that treatment and the start of study therapy.

3. Previous gemcitabine therapy for advanced pancreatic cancer. Patients who have had chemotherapy within 4 weeks, nitrosoureas/mitomycin C within 6 weeks, or monoclonal antibody within 6 weeks prior to planned initiation of study treatment.

4. prior treatment with a small molecule kinase inhibitor or a hormonal therapy within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.

5. have received an investigational agent within 28 days of the first dose of study treatment or 5 half-lives of the compound or active metabolite, whichever is longer.

6. have received radiation therapy within 14 days of study treatment.

7. have not recovered from toxicity due to all prior therapies (i.e., return to pretherapy baseline or to CTCAE Grade 0 or 1) except alopecia and non-clinically significant AEs.

8. known brain metastases.

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

• University of Michigan Rogel Cancer Center

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT01663272
• Other Study ID Numbers: UMCC 2011.105; HUM 62927
• First Posted: Aug 13, 2012
• Last Update Posted: Sep 19, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by University of Michigan Rogel Cancer Center: oncology; pancrease
• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine

Study Results

Participant Flow

Arm/Group Title	Dose Level -1	Dose Level 1	Dose Level 2
Arm/Group Description	20 mg of cabozantinib PO daily administered days -7 until disease progression, intolerable adverse event(s) or patient choice. 800mg/m^2 of gemcitabine administered intravenously on days 1, 8, and 15 every 28 days.	20 mg of cabozantinib PO daily administered days -7 until disease progression, intolerable adverse event(s) or patient choice. 1000mg/m^2 of gemcitabine administered intravenously on days 1, 8, and 15 every 28 days.	40 mg of cabozantinib PO daily administered days -7 until disease progression, intolerable adverse event(s) or patient choice. 1000mg/m^2 of gemcitabine administered intravenously on days 1, 8, and 15 every 28 days.
Period Title: Overall Study
STARTED	5	6	1
COMPLETED	5	6	1
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Cabozantinib With Gemcitabine
Arm/Group Description	Patients received daily oral cabozantinib, at 20mg or 40mg, administered days -7 until disease progression, intolerable adverse event(s) or patient choice AND Gemcitabine at 800mg/m^2 or 1000mg/m^2 administered intravenously on days 1, 8, and 15 every 28 days.
Overall Participants	12
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.5
Sex: Female, Male (Count of Participants)
Female	6 50%
Male	6 50%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose
Description	The MTD is defined at the highest dose level at which ≤25% of patients experience a dose-limiting toxicity (DLT).
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cabozantinib With Gemcitabine
Arm/Group Description	The Study Treatment Period will consist of continued treatment during which time patients will receive cabozantinib and gemcitabine until either disease progression or the occurrence of unacceptable drug-related toxicity Cabozantinib: Daily oral cabozantinib (20mg OR 40mg) administered days -7 until disease progression, intolerable adverse event(s) or patient choice. Gemcitabine: Gemcitabine (800mg/m^2 OR 1000mg/m^2) administered intravenously on days 1, 8, and 15 every 28 days.
Measure Participants	12
Number [mg]	NA

2. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	Progression-free survival (PFS, a secondary endpoint) will be calculated from day-7 of cycle 1 of study treatment, until documented disease progression or death. Patients removed from treatment for progression or other reasons will be followed for 30 days after their last dose.
Time Frame	day-7 of cycle 1 until 30 days post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cabozantinib With Gemcitabine
Arm/Group Description	The Study Treatment Period will consist of continued treatment during which time patients will receive cabozantinib and gemcitabine until either disease progression or the occurrence of unacceptable drug-related toxicity Cabozantinib: Daily oral cabozantinib (20mg OR 40mg) administered days -7 until disease progression, intolerable adverse event(s) or patient choice. Gemcitabine: Gemcitabine (800mg/m^2 OR 1000mg/m^2) administered intravenously on days 1, 8, and 15 every 28 days.
Measure Participants	12
Median (95% Confidence Interval) [months]	4.7

Adverse Events

Arm/Group Title	Cabozantinib With Gemcitabine
Arm/Group Description	Adverse events were pooled for all treated patients and were not collected by dose level. Patients received daily oral cabozantinib, at 20mg or 40mg, administered days -7 until disease progression, intolerable adverse event(s) or patient choice AND Gemcitabine at 800mg/m^2 or 1000mg/m^2 administered intravenously on days 1, 8, and 15 every 28 days.
All Cause Mortality
	Cabozantinib With Gemcitabine
	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)
Serious Adverse Events
	Cabozantinib With Gemcitabine
	Affected / at Risk (%)	# Events
Total	4/12 (33.3%)
Gastrointestinal disorders
Gastrointestinal Fistula	1/12 (8.3%)	1
Bile Duct Stenosis	1/12 (8.3%)	1
General disorders
Death, NOS	1/12 (8.3%)	1
Infections and infestations
Flu Like Symptoms	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Cabozantinib With Gemcitabine
	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)
Blood and lymphatic system disorders
Anemia	5/12 (41.7%)	10
Ear and labyrinth disorders
Tinnitus	1/12 (8.3%)	1
Gastrointestinal disorders
Abdominal distension	1/12 (8.3%)	1
Abdominal pain	7/12 (58.3%)	7
Anal hemorrhage	1/12 (8.3%)	2
Bloating	1/12 (8.3%)	1
Constipation	4/12 (33.3%)	4
Diarrhea	4/12 (33.3%)	7
Dyspepsia	1/12 (8.3%)	1
Mucositis oral	1/12 (8.3%)	1
Nausea	7/12 (58.3%)	9
Oral pain	1/12 (8.3%)	1
Rectal pain	1/12 (8.3%)	1
Vomiting	3/12 (25%)	5
General disorders
Chills	3/12 (25%)	3
Edema limbs	2/12 (16.7%)	2
Fatigue	8/12 (66.7%)	11
Fever	3/12 (25%)	3
Localized edema	2/12 (16.7%)	2
Pain	2/12 (16.7%)	2
Infections and infestations
Biliary tract infection	1/12 (8.3%)	1
Papulopustular rash	1/12 (8.3%)	1
Pharyngitis	1/12 (8.3%)	1
Sepsis	1/12 (8.3%)	1
Upper respiratory infection	1/12 (8.3%)	1
Investigations
Alanine aminotransferase increased	11/12 (91.7%)	28
Alkaline phosphatase increased	7/12 (58.3%)	11
Aspartate aminotransferase increased	9/12 (75%)	16
Blood bilirubin increased	3/12 (25%)	8
Creatinine increased	2/12 (16.7%)	2
Lipase increased	1/12 (8.3%)	4
Lymphocyte count decreased	5/12 (41.7%)	9
Neutrophil count decreased	9/12 (75%)	21
Platelet count decreased	10/12 (83.3%)	24
Weight loss	1/12 (8.3%)	1
White blood cell decreased	10/12 (83.3%)	31
Metabolism and nutrition disorders
Anorexia	4/12 (33.3%)	4
Hypercalcemia	1/12 (8.3%)	1
Hyperglycemia	4/12 (33.3%)	10
Hyperkalemia	3/12 (25%)	3
Hypernatremia	1/12 (8.3%)	1
Hypoalbuminemia	2/12 (16.7%)	6
Hypocalcemia	4/12 (33.3%)	9
Hypoglycemia	2/12 (16.7%)	3
Hypokalemia	3/12 (25%)	5
Hyponatremia	3/12 (25%)	3
Hypophosphatemia	6/12 (50%)	8
Musculoskeletal and connective tissue disorders
Back pain	1/12 (8.3%)	1
Generalized muscle weakness	2/12 (16.7%)	2
Musculoskeletal and connective tissue disorder - Other	1/12 (8.3%)	1
Pain in extremity	1/12 (8.3%)	1
Nervous system disorders
Dizziness	1/12 (8.3%)	1
Dysgeusia	1/12 (8.3%)	1
Headache	3/12 (25%)	3
Psychiatric disorders
Anxiety	4/12 (33.3%)	4
Renal and urinary disorders
Proteinuria	2/12 (16.7%)	3
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/12 (8.3%)	1
Cough	1/12 (8.3%)	1
Dyspnea	2/12 (16.7%)	2
Epistaxis	1/12 (8.3%)	2
Hoarseness	1/12 (8.3%)	1
Nasal congestion	1/12 (8.3%)	1
Wheezing	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/12 (8.3%)	1
Rash maculo-papular	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders - Other	1/12 (8.3%)	1
Vascular disorders
Hypertension	5/12 (41.7%)	5
Hypotension	1/12 (8.3%)	1

Limitations/Caveats

The MTD could not be determined as too many patients experienced toxicity.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.