RAD001 and Temozolomide in Patients With Advanced Pancreatic Neuroendocrine Tumors

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00576680
• Collaborator: Beth Israel Deaconess Medical Center (Other), Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), Novartis (Industry), Schering-Plough (Industry)
• Enrollment: 43
• Locations: 3
• Arm: 1
• Duration (Months): 130.9
• Patients Per Site: 14.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This research study will test the safety of RAD001 in combination with temozolomide.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Neuroendocrine Tumor	Drug: RAD001; Drug: Temozolomide	Phase 1/Phase 2

Detailed Description

• Participants will take RAD001 by mouth daily. They will also take temozolomide by mouth daily for one week, followed by a one-week break period. This one-week on/one week off schedule for temozolomide will continue for the duration of the treatment.

• After the first month of treatment, there will be a 7-day observation period during which no study medication will be taken to observe for any side effects.

• During all treatment cycles (1 cycle is 28 days in length) participants will have a physical exam and will be asked questions about their general health and specific questions about any problems they may be experiencing. Initially, participants will come in every other week. At each of these visits, blood work will be taken to monitor the participants health.

• After every 2 months of treatment, participants will have a CT scan or MRI done to see how the medication is working.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of RAD001 in Combination With Temozolomide in Patients With Advanced Pancreatic Neuroendocrine Tumors
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Mar 29, 2019
• Actual Study Completion Date: Mar 29, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Temozolomide with RAD001	Drug: RAD001; Given orally once a day; Drug: Temozolomide; Taken orally once a day for one week followed by a one-week break period; Other Names: Temodar

Outcome Measures

Primary Outcome Measures

1. Response Rate [2 years]

   To determine the objective response rate by RECIST criteria of RAD001 in combination with temozolomide in patients with advanced pancreatic neuroendocrine tumors. Partial response (PR) by these criteria is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Progressive disease (PD) is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD) is defined as neither sufficient decrease to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.

Secondary Outcome Measures

1. Progression-free Survival [2 years]

   To determine progression-free survival when RAD001 is given in combination with temozolomide in patients with advanced pancreatic neuroendocrine tumors. Progression-free survival is defined as time from start of therapy until disease progression, as defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions, or death.

2. To Determine the Safety and Tolerability of This Drug Combination. [2 years]

   To determine the safety and tolerability of RAD001 when given in combination with temozolomide in patients with advanced pancreatic neuroendocrine tumors.

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 pancreatic neuroendocrine tumor

• Radiologic, operative, or pathology reports should document a pancreatic location of tumor

• Patients must have confirmed low-grade or intermediate-grade neuroendocrine carcinoma

• Patients must have at least one measurable site of disease according to RECIST criteria that has not been preciously irradiated

• 18 years of age or older

• Minimum of two weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy

• Prior treatment with chemotherapy is allowed, with the exception of prior treatment with temozolomide or dacarbazine

• No Prior therapy with RAD001 or any other mTOR inhibitor

• ECOG Performance status 0,1 or 2

• Life expectancy 12 weeks or more

• Adequate bone marrow, liver and renal function as outlined in the protocol

• Negative serum pregnancy test

• Fasting serum cholesterol as outlined in protocol

Exclusion Criteria:

• Prior treatment with any investigational drug within the preceding 4 weeks

• Chronic treatment with systemic steroids or another immunosuppressive agent

• Patients should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

• Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinoma of the skin

• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study

• Women who are pregnant or breast feeding

• Patients who have received prior treatment with an mTOR inhibitor or temozolomide

• Patients with known hypersensitivity to RAD001 or other rapamycins or to its excipients

• History of noncompliance to medical regimens

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Beth Israel Deaconess Medical Center
• Brigham and Women's Hospital
• Massachusetts General Hospital
• Novartis
• Schering-Plough

Investigators

• Principal Investigator: Jennifer Chan, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 7, 2019

More Information

Publications

None provided.

• Responsible Party: Jennifer Chan, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00576680
• Other Study ID Numbers: 07-325
• First Posted: Dec 19, 2007
• Last Update Posted: Jul 9, 2020
• Last Verified: Jun 1, 2020

• Keywords provided by Jennifer Chan, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute: RAD001; temozolomide
• Additional relevant MeSH terms: Neuroendocrine Tumors; Adenoma, Islet Cell; Temozolomide; Everolimus

Study Results

Participant Flow

Arm/Group Title	Temozolomide and Everolimus
Arm/Group Description	Temozolomide was administered to all patients at a starting dose of 150 mg/m2 on days 1 to 7 and days 15 to 21 of a 28-day cycle. Everolimus was administered together with temozolomide in 2 dose cohorts: 1) 5 mg daily and 2) 10 mg daily.
Period Title: Overall Study
STARTED	43
COMPLETED	43
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Temozolomide and Everolimus
Arm/Group Description	Temozolomide was administered to all patients at a starting dose of 150 mg/m2 on days 1 to 7 and days 15 to 21 of a 28-day cycle. Everolimus was administered together with temozolomide in 2 dose cohorts: 1) 5 mg daily and 2) 10 mg daily.
Overall Participants	43
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	17 39.5%
Male	26 60.5%
Race and Ethnicity Not Collected (Count of Participants)

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	To determine the objective response rate by RECIST criteria of RAD001 in combination with temozolomide in patients with advanced pancreatic neuroendocrine tumors. Partial response (PR) by these criteria is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Progressive disease (PD) is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD) is defined as neither sufficient decrease to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Temozolomide and Everolimus
Arm/Group Description	Temozolomide was administered to all patients at a starting dose of 150 mg/m2 on days 1 to 7 and days 15 to 21 of a 28-day cycle. Everolimus was administered together with temozolomide in 2 dose cohorts: 1) 5 mg daily and 2) 10 mg daily.
Measure Participants	40
Count of Participants [Participants]	16 37.2%

2. Secondary Outcome

Title	Progression-free Survival
Description	To determine progression-free survival when RAD001 is given in combination with temozolomide in patients with advanced pancreatic neuroendocrine tumors. Progression-free survival is defined as time from start of therapy until disease progression, as defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions, or death.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Temozolomide and Everolimus
Arm/Group Description	Temozolomide was administered to all patients at a starting dose of 150 mg/m2 on days 1 to 7 and days 15 to 21 of a 28-day cycle. Everolimus was administered together with temozolomide in 2 dose cohorts: 1) 5 mg daily and 2) 10 mg daily.
Measure Participants	43
Median (95% Confidence Interval) [months]	15.4

3. Secondary Outcome

Title	To Determine the Safety and Tolerability of This Drug Combination.
Description	To determine the safety and tolerability of RAD001 when given in combination with temozolomide in patients with advanced pancreatic neuroendocrine tumors.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Temozolomide and Everolimus
Arm/Group Description	Temozolomide was administered to all patients at a starting dose of 150 mg/m2 on days 1 to 7 and days 15 to 21 of a 28-day cycle. Everolimus was administered together with temozolomide in 2 dose cohorts: 1) 5 mg daily and 2) 10 mg daily.
Measure Participants	43
Grade 3 or 4 Lymphopenia	19 44.2%
Grade 3 or 4 thrombocytopenia	7 16.3%
Grade 3 or 4 mucositis	1 2.3%
Grade 3 or 4 hyperglycemia	8 18.6%
Grade 3 or 4 AST Increase	4 9.3%
Grade 3 or 4 Leukocyte decrease	7 16.3%

Adverse Events

Time Frame	Participants were followed for development of adverse events for the entire duration while receiving treatment and for 30 days following their last dose of study treatment. Patients in this trial received a median of 8.5 four-week treatment cycles (range, 1-28). Each participant was followed for adverse events for 30 days following his or her last dose of study treatment.
Adverse Event Reporting Description	All-grade adverse events possible or definitely related to treatment are reported.
Arm/Group Title	Temozolomide and Everolimus
Arm/Group Description	Temozolomide was administered to all patients at a starting dose of 150 mg/m2 on days 1 to 7 and days 15 to 21 of a 28-day cycle. Everolimus was administered together with temozolomide in 2 dose cohorts: 1) 5 mg daily and 2) 10 mg daily.
All Cause Mortality
	Temozolomide and Everolimus
	Affected / at Risk (%)	# Events
Total	2/43 (4.7%)
Serious Adverse Events
	Temozolomide and Everolimus
	Affected / at Risk (%)	# Events
Total	15/43 (34.9%)
Blood and lymphatic system disorders
thrombocytopenia	2/43 (4.7%)	2
neutropenia	2/43 (4.7%)	2
anemia	0/43 (0%)	0
lymphopenia	8/43 (18.6%)	10
Investigations
hypocalcemia	1/43 (2.3%)	1
hypophosphatemia	1/43 (2.3%)	1
Renal and urinary disorders
creatinine	0/43 (0%)	0
Respiratory, thoracic and mediastinal disorders
pneumonitis	1/43 (2.3%)	1
dyspnea	1/43 (2.3%)	1
Other (Not Including Serious) Adverse Events
	Temozolomide and Everolimus
	Affected / at Risk (%)	# Events
Total	43/43 (100%)
Blood and lymphatic system disorders
Lymphocytopenia	22/43 (51.2%)
Endocrine disorders
Hyperglycemia	31/43 (72.1%)
Gastrointestinal disorders
Nausea	33/43 (76.7%)
Mucositis	27/43 (62.8%)
General disorders
Fatigue	33/43 (76.7%)
Hypercholesterolemia	18/43 (41.9%)

Limitations/Caveats

[Not Specified]

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.