A Study of Axitinib in Advanced Carcinoid Tumors

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01435122
• Collaborator: National Comprehensive Cancer Network (Other), Pfizer (Industry)
• Enrollment: 30
• Locations: 2
• Arm: 1
• Actual Duration (Months): 75.7
• Patients Per Site: 15
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The main purpose of this study is to see whether Axitinib will help prolong the time that the patient's carcinoid tumors remain stable, and to examine their treatment response through testing. Researchers also want to find out if Axitinib is safe and tolerable.

Condition or Disease	Intervention/Treatment	Phase
Carcinoid Tumor	Drug: Axitinib	Phase 2

Detailed Description

This is a bi-institutional, prospective phase II, open-label study. The target population is comprised of adult patients with histologically confirmed unresectable or metastatic carcinoid tumors. Carcinoid tumors are defined as well to moderately differentiated neuroendocrine tumors of the digestive tract and lungs. Patients with metastatic carcinoid tumors of unknown primary as well as rare primaries (renal, ovarian, thymic, hepatic) will also be eligible. Patients will be drawn from two institutions Moffitt Cancer Center (MCC) and The University of California, San Francisco (UCSF).

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Axitinib in Advanced Carcinoid Tumors
• Actual Study Start Date: Oct 25, 2011
• Actual Primary Completion Date: Jan 11, 2017
• Actual Study Completion Date: Feb 13, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Axitinib Administration The investigational drug used in this study is axitinib, and is available as tablets. You will take the tablet orally with food. Doses should be taken around 12 hours apart continuously, without scheduled breaks. If you vomit anytime after taking a dose do not take another tablet to "make up the dose" but instead continue taking your next dose as planned. Any missed dose may be taken late (up to 3 hours before the next scheduled dose); otherwise it should be skipped. If doses are missed or vomited, please keep track of this and report at your next visit.

Drug: Axitinib; Axitinib Administration as outlined in Arm description; Other Names: AG013736 selective inhibitor of receptor tyrosine kinases

Outcome Measures

Primary Outcome Measures

1. Rate of Progression Free Survival (PFS) [12 Months]

   Progression-free survival rate at 12 months. PFS: determined as the time from administration of the initial dose of axitinib until objective tumor progression using Response Evaluation Criteria In Solid Tumors (RECIST), or death. Progressive Disease (PD) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Stable Disease (SD): Neither sufficient shrinkage to qualify for Partial Response (PR) nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

2. Median Progression Free Survival [Up to 36 Months]

   Post follow-up progression free survival at time of analysis.

Secondary Outcome Measures

1. Tumor Response Rate [12 Months]

   Tumor response rate using RECIST. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

2. 24 Month Overall Survival (OS) Rate [24 months]

   Overall survival by Kaplan Meier, determined from the time of drug administration to death from any cause. The effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis.

3. Time to Treatment Failure [12 Months]

   Time to Treatment Failure: Time from administration of the initial dose of axitinib until study discontinuation for any reason (e.g., disease progression, toxicity, death, withdrawal of consent).

4. Occurrence of Possibly Related Adverse Events (AEs) [12 Months]

   Grade 2 through 4 toxicities considered at least possibly related to treatment. Percentage of participants affected per category. Safety assessments will consist of monitoring and recording all adverse events and serious adverse events, the regular monitoring of hematology and blood chemistry parameters and regular physical examinations. Adverse events will be evaluated continuously throughout the study. Safety and tolerability will be assessed according to the National Institute of Health/National Cancer Institute (NIH/NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Locally unresectable or metastatic well-and moderately-differentiated (low- or intermediate- grade) neuroendocrine tumors of the aerodigestive tract (e.g. foregut, midgut, and hindgut) and unknown primary site as well as rare primary sites (renal, ovarian, thymic, hepatic); Otherwise known as typical or atypical carcinoid tumors

• Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) Criteria

• Functional or nonfunctional tumors allowed

• Evidence of progressive disease within 12 months of study entry

• Adequate hepatic function: total bilirubin ≤1.5 x upper limit of normal (ULN)mg/dl; aspartic transaminase (AST) ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases)

• Adequate renal function: serum creatinine ≤ 1.5 x ULN

• Adequate bone marrow function: absolute neutrophil count ≥ 1,500/mm³; platelets ≥75,000/mm³

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels ≤1.5 x ULN (unless patients receiving coumadin anticoagulation in which case a stable international normalization ration (INR) of 2-3 is required).

• Urine protein <2+proteinuria (or <2 g proteinuria /24 hr)

• Prior somatostatin-analog therapy required in patients with midgut carcinoid tumors

• Minimum 4 weeks since completion of prior treatment (investigational or other). Prior treatment with chemotherapy, radiotherapy, hepatic artery embolization, surgery or other therapeutic agents is allowed.

• Treatment related toxicity should have returned to baseline and/or ≤grade 1 prior to study treatment.

• Prior or concurrent therapy with somatostatin analogs is permitted for the control of hormone-mediated symptoms, provided patient has been on a stable dose for at least 2 months and progressive disease on somatostatin analogs (SSTa) has been documented

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to treatment.

• Ability to sign informed consent

• Willingness and ability to comply with scheduled visits, laboratory tests and other study procedures

Exclusion Criteria:

• Poorly differentiated, high-grade (e.g. small cell or large cell) neuroendocrine carcinomas are excluded.

• Pancreatic neuroendocrine tumors (NETs), paragangliomas, pheochromocytomas and medullary thyroid cancers are excluded.

• Adenocarcinoid tumors and goblet cell carcinoid tumors are excluded.

• Prior antiangiogenic therapy with a dedicated vascular endothelial growth factor (VEGF) pathway inhibitor

• Clinically apparent central nervous system metastases

• Any of the following within 12 months prior to study: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack

• Deep venous thrombosis or pulmonary embolism within 6 months of study

• Major surgery 4 weeks prior to enrollment

• Inability to take oral medication or prior surgical procedures affecting absorption (including total gastric resection)

• Active gastrointestinal bleeding, if transfusion dependent

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days

• History of pulmonary hemorrhage or evidence of significant hemoptysis

• History of serious non-healing wound, ulcer, or bone fracture within the past 28 days

• Pre-existing thyroid abnormality allowed provided thyroid function can be controlled with medication.

• Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, etc.)

• Current use or anticipated need for treatment with drugs that are known inducers of CYP3AR or CYP1A2 (i.e carbamazepine, dexamethasone, omeprazole, phenobarbital, phenytoin, rifampin, St. John's Wart, etc.)

• Uncontrolled serious medical or psychiatric illness. Patients with a "currently active" second malignancy other than non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer (staged pathological tumor-2 (pT2) with Gleason Score ≤ 6 and postoperative prostatic specific antigen (PSA) < 0.5 ng/mL), or other adequately treated carcinoma-in-situ are ineligible. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥3 years.

• Pregnant or lactating women, or adults of reproductive potential who are not using effective birth-control methods.

• Prior antitumor therapy within 4 weeks of enrollment (with exception of somatostatin analogs)

• Liver-directed therapy within 2 months of enrollment. Prior treatment with radiotherapy (including radio-labeled spheres and/or cyberknife, hepatic arterial embolization (with or without chemotherapy) or cryotherapy/ablation is allowed if these therapies did not affect the areas of measurable disease being used for this protocol or if progressive disease can be documented in the previously treated area.

• Recent infection requiring systemic anti-infective treatment that was completed ≤14 days prior to enrollment (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection)

• Uncontrolled hypertension (blood-pressure >140/90). Patient with baseline hypertension may be eligible after initiation of antihypertensive therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco (UCSF)	San Francisco	California	United States	94115
2	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• National Comprehensive Cancer Network
• Pfizer

Investigators

• Principal Investigator: Jonathan Strosberg, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT01435122
• Other Study ID Numbers: MCC-16692
• First Posted: Sep 15, 2011
• Last Update Posted: Oct 2, 2018
• Last Verified: Aug 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: progressive advanced carcinoid tumors; advanced; unresectable; metastatic; cancerous tumors; neuroendocrine; digestive tract; lungs; renal; ovarian; thymic; hepatic
• Additional relevant MeSH terms: Carcinoid Tumor; Axitinib

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida and the UCSF Comprehensive Cancer Center, University of California, San Francisco, California, from October 2011 through January 2014.

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Period Title: Overall Study
STARTED	30
COMPLETED	22
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 53.3%
>=65 years	14 46.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	17 56.7%
Male	13 43.3%
Region of Enrollment (participants) [Number]
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	Rate of Progression Free Survival (PFS)
Description	Progression-free survival rate at 12 months. PFS: determined as the time from administration of the initial dose of axitinib until objective tumor progression using Response Evaluation Criteria In Solid Tumors (RECIST), or death. Progressive Disease (PD) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Stable Disease (SD): Neither sufficient shrinkage to qualify for Partial Response (PR) nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Measure Participants	30
Number [percentage of participants]	74.5 248.3%

2. Primary Outcome

Title	Median Progression Free Survival
Description	Post follow-up progression free survival at time of analysis.
Time Frame	Up to 36 Months

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Measure Participants	30
Median (95% Confidence Interval) [months]	26.7

3. Secondary Outcome

Title	Tumor Response Rate
Description	Tumor response rate using RECIST. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

All participants evaluable at time of analysis.

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Measure Participants	22
Partial response	1 3.3%
Stable disease	21 70%

4. Secondary Outcome

Title	24 Month Overall Survival (OS) Rate
Description	Overall survival by Kaplan Meier, determined from the time of drug administration to death from any cause. The effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Measure Participants	30
Number [percentage of participants]	74.3 247.7%

5. Secondary Outcome

Title	Time to Treatment Failure
Description	Time to Treatment Failure: Time from administration of the initial dose of axitinib until study discontinuation for any reason (e.g., disease progression, toxicity, death, withdrawal of consent).
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Measure Participants	30
Median (95% Confidence Interval) [months]	9.6

6. Secondary Outcome

Title	Occurrence of Possibly Related Adverse Events (AEs)
Description	Grade 2 through 4 toxicities considered at least possibly related to treatment. Percentage of participants affected per category. Safety assessments will consist of monitoring and recording all adverse events and serious adverse events, the regular monitoring of hematology and blood chemistry parameters and regular physical examinations. Adverse events will be evaluated continuously throughout the study. Safety and tolerability will be assessed according to the National Institute of Health/National Cancer Institute (NIH/NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
Measure Participants	30
Hypertension	87 290%
Abdominal pain	17 56.7%
Diarrhea	17 56.7%
Nausea	13 43.3%
Vomiting	7 23.3%
Mucositis	3 10%
Oral pain	3 10%
Headache	20 66.7%
Confusion	3 10%
Insomnia	3 10%
Syncope	3 10%
Anxiety	3 10%
Intracranial hemorrhage	3 10%
Fatigue	27 90%
Weight loss	6 20%
Anorexia	3 10%
Myalgia	3 10%
Dehydration	10 33.3%
Hypothyroidism	3 10%
Increased transaminases	3 10%
Increased alkaline phosphatase	10 33.3%
Increased gamma-glutamyl transferase	3 10%
Urinary tract infection	3 10%
Right ventricular dysfunction	3 10%
Pain in extremity	3 10%
Hand-foot syndrome	2 6.7%

Adverse Events

Time Frame	3 years, 10 months
Arm/Group Title	Axitinib Administration
Arm/Group Description	The investigational drug used in this study is axitinib, and is available as tablets.
All Cause Mortality
	Axitinib Administration
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Axitinib Administration
	Affected / at Risk (%)	# Events
Total	12/30 (40%)
Blood and lymphatic system disorders
Anemia	1/30 (3.3%)	1
Cardiac disorders
Aortic valve disease	1/30 (3.3%)	1
Gastrointestinal disorders
Abdominal pain	3/30 (10%)	3
Colitis	2/30 (6.7%)	2
Constipation	1/30 (3.3%)	1
Diarrhea	1/30 (3.3%)	1
Ileus	1/30 (3.3%)	1
Nausea	2/30 (6.7%)	2
Pancreatitis	2/30 (6.7%)	3
Rectal hemorrhage	1/30 (3.3%)	1
Rectal ulcer	1/30 (3.3%)	1
Small intestinal obstruction	1/30 (3.3%)	1
Vomiting	2/30 (6.7%)	2
General disorders
Chills	1/30 (3.3%)	3
Fatigue	3/30 (10%)	3
Fever	1/30 (3.3%)	3
Hepatobiliary disorders
Bile duct stenosis	1/30 (3.3%)	1
Investigations
Blood bilirubin increased	1/30 (3.3%)	1
Metabolism and nutrition disorders
Anorexia	1/30 (3.3%)	1
Dehydration	2/30 (6.7%)	2
Hypomagnesemia	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/30 (3.3%)	1
Nervous system disorders
Intracranial hemorrhage	1/30 (3.3%)	1
Lethargy	1/30 (3.3%)	1
Nervous system disorders - Other, neurologic changes	1/30 (3.3%)	1
Seizure	1/30 (3.3%)	1
Psychiatric disorders
Confusion	1/30 (3.3%)	1
Renal and urinary disorders
Acute kidney injury	2/30 (6.7%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/30 (6.7%)	3
Vascular disorders
Hypertension	2/30 (6.7%)	2
Hypotension	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Axitinib Administration
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Anemia	7/30 (23.3%)	7
Endocrine disorders
Hypothyroidism	3/30 (10%)	3
Eye disorders
Dry eye	2/30 (6.7%)	3
Gastrointestinal disorders
Abdominal pain	8/30 (26.7%)	16
Anal mucositis	2/30 (6.7%)	6
Anal pain	2/30 (6.7%)	3
Bloating	3/30 (10%)	3
Constipation	7/30 (23.3%)	19
Diarrhea	12/30 (40%)	27
Dry mouth	4/30 (13.3%)	4
Dyspepsia	3/30 (10%)	4
Flatulence	3/30 (10%)	4
Gastrointestinal disorders - Other	3/30 (10%)	5
Hemorrhoids	5/30 (16.7%)	7
Mucositis oral	5/30 (16.7%)	7
Nausea	12/30 (40%)	19
Oral pain	3/30 (10%)	6
Rectal hemorrhage	2/30 (6.7%)	2
Rectal pain	2/30 (6.7%)	2
Vomiting	6/30 (20%)	8
General disorders
Edema limbs	3/30 (10%)	4
Fatigue	17/30 (56.7%)	32
General disorders and administration site conditions - Other, specify	3/30 (10%)	7
Non-cardiac chest pain	2/30 (6.7%)	3
Pain	2/30 (6.7%)	2
Infections and infestations
Urinary tract infection	2/30 (6.7%)	3
Investigations
Alanine aminotransferase increased	4/30 (13.3%)	5
Alkaline phosphatase increased	4/30 (13.3%)	8
Blood bilirubin increased	3/30 (10%)	5
Creatinine increased	4/30 (13.3%)	4
Platelet count decreased	8/30 (26.7%)	18
Weight loss	10/30 (33.3%)	10
Metabolism and nutrition disorders
Anorexia	9/30 (30%)	9
Dehydration	2/30 (6.7%)	2
Hyperglycemia	10/30 (33.3%)	22
Hyperkalemia	4/30 (13.3%)	8
Hypocalcemia	2/30 (6.7%)	5
Hypoglycemia	3/30 (10%)	6
Hypokalemia	4/30 (13.3%)	6
Hyponatremia	3/30 (10%)	3
Musculoskeletal and connective tissue disorders
Back pain	6/30 (20%)	10
Myalgia	5/30 (16.7%)	6
Pain in extremity	2/30 (6.7%)	4
Nervous system disorders
Dizziness	5/30 (16.7%)	7
Headache	14/30 (46.7%)	21
Paresthesia	2/30 (6.7%)	2
Psychiatric disorders
Anxiety	4/30 (13.3%)	4
Confusion	2/30 (6.7%)	3
Depression	4/30 (13.3%)	4
Insomnia	7/30 (23.3%)	11
Renal and urinary disorders
Proteinuria	4/30 (13.3%)	7
Renal and urinary disorders - Other	2/30 (6.7%)	3
Reproductive system and breast disorders
Reproductive system and breast disorders - Other	2/30 (6.7%)	2
Respiratory, thoracic and mediastinal disorders
Cough	4/30 (13.3%)	4
Dyspnea	2/30 (6.7%)	3
Epistaxis	2/30 (6.7%)	4
Hoarseness	10/30 (33.3%)	12
Nasal congestion	2/30 (6.7%)	2
Respiratory, thoracic and mediastinal disorders - Other	3/30 (10%)	4
Sore throat	2/30 (6.7%)	2
Skin and subcutaneous tissue disorders
Alopecia	2/30 (6.7%)	2
Dry skin	3/30 (10%)	3
Palmar-plantar erythrodysesthesia syndrome	5/30 (16.7%)	6
Rash maculo-papular	2/30 (6.7%)	2
Skin and subcutaneous tissue disorders - Other	3/30 (10%)	4
Vascular disorders
Hematoma	2/30 (6.7%)	3
Hypertension	26/30 (86.7%)	266

Limitations/Caveats

Results are limited by a relatively high rate of participant withdrawal before progression due to toxicity. Post analysis, 2 participants are still on study at UCSF.

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.