A Study of Metformin With or Without Rapamycin as Maintenance Therapy After Induction Chemotherapy in Subjects With Pancreatic Cancer

• ClinicalTrials.gov Identifier: NCT02048384
• Recruitment Status: Completed
• First Posted: January 29, 2014
• Last Update Posted: April 12, 2021
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: Stand Up To Cancer
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: January 23, 2014
• First Posted Date: January 29, 2014
• Last Update Posted Date: April 12, 2021
• Actual Study Start Date: June 10, 2014
• Actual Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2017)

safety and feasibility [ Time Frame: 1 year ]

To determine the safety and feasibility of administering metformin with or without rapamycin in subjects with metastatic pancreatic ductal adenocarcinoma (PDA) after disease stabilization on chemotherapy.

Original Primary Outcome Measures (submitted: January 27, 2014)

safety and feasibility [ Time Frame: 1 year ]

To determine the safety and feasibility of administering metformin with or without rapamycin in subjects with metastatic pancreatic ductal adenocarcinoma (PDA) after disease stabilization on chemotherapy. This is an exploratory study designed to assess the safety and feasibility of the use of maintenance therapy in the first line treatment of subjects with metastatic pancreatic cancer. The study will be continuously monitoring for adverse events in each arm. If the unacceptable toxicity events appear to be higher than 30%, we will temporarily halt the study pending dose modification. Specifically, we will apply Bayesian toxicity monitoring. In determining feasibility of enrolling patients onto a maintenance study, if less than 6 patients are enrolled in the first 12 months investigators will re-evaluate the strategy. Feasibility will also be assessed by the ability for the study to complete enrollment within 24 months after the first subject is enrolled.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: May 11, 2017)

• FDG uptake [ Time Frame: 1 year ]
  To evaluate fludeoxyglucose (FDG) uptake in metastatic PDA subjects treated with metformin with or without rapamycin.
• mTOR activity [ Time Frame: 1 year ]
  To measure mammalian target of rapamycin (mTOR) activity in peripheral blood mononuclear cells (PBMC) of subjects treated with metformin with or without rapamycin.
• estimation of RR, TTP, PFS, OS [ Time Frame: 1 year ]
  To estimate response rate (RR), time to progression (TTP), progression-free survival (PFS) and overall survival (OS) in subjects with metastatic PDA treated with metformin with or without rapamycin.
• CA19-9 measurement [ Time Frame: 1 year ]
  To measure tumor marker kinetics (CA 19-9) in subjects treated with metformin with or without rapamycin.

Original Other Pre-specified Outcome Measures (submitted: January 27, 2014)

• FDG uptake [ Time Frame: 1 year ]
  To evaluate fludeoxyglucose (FDG) uptake in metastatic PDA subjects treated with metformin with or without rapamycin.
• H1F1 & glutaminate expression [ Time Frame: 1 year ]
  To measure HIF1 and glutaminate expression in tumors of subjects treated with metformin with or without rapamycin.
• histological evaluation [ Time Frame: 1 year ]
  To evaluate extracellular matrix by histology in tumors of subjects treated with metformin with or without rapamycin.
• mTOR activity [ Time Frame: 1 year ]
  To measure mammalian target of rapamycin (mTOR) activity in peripheral blood mononuclear cells (PBMC) of subjects treated with metformin with or without rapamycin.
• estimation of RR, TTP, PFS, OS [ Time Frame: 1 year ]
  To estimate response rate (RR), time to progression (TTP), progression-free survival (PFS) and overall survival (OS) in subjects with metastatic PDA treated with metformin with or without rapamycin.
• CA19-9 measurement [ Time Frame: 1 year ]
  To measure tumor marker kinetics (CA 19-9) in subjects treated with metformin with or without rapamycin.

Descriptive Information

• Brief Title: A Study of Metformin With or Without Rapamycin as Maintenance Therapy After Induction Chemotherapy in Subjects With Pancreatic Cancer
• Official Title: An Exploratory Study of Metformin With or Without Rapamycin as Maintenance Therapy After Induction Chemotherapy in Subjects With Metastatic Pancreatic Adenocarcinoma
• Brief Summary: This is a phase 1b, multi-center, open label, randomized study to evaluate the safety and feasibility of administering metformin with or without rapamycin after disease stabilization on chemotherapy in subjects with metastatic PDA.

Detailed Description

Subjects with metastatic PDA who have received FOLFIRINOX or a gemcitabine-containing regimen and have achieved stable disease or better will be enrolled onto this study. Subjects should have had at least 6 months of chemotherapy and decline continuation of chemotherapy and should have stable disease or better on 2 scans taken at least 6 weeks apart. If applicable, subjects should also have a stable or declining CA19-9.

Twenty-two subjects will be randomized in a 1:1 ratio to metformin (Arm A) or metformin + rapamycin (Arm B). Subjects will be stratified according to their prior chemotherapy regimen: FOLFIRINOX or a gemcitabine-containing regimen.

Treatments will be administered orally on a 28 day cycle. Metformin will be administered 850mg twice daily and rapamycin will be administered 4mg daily.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Pancreatic Adenocarcinoma

Intervention

• Drug: metformin alone (Arm A)
  metformin alone
  Other Name: Glumetza, Fortamet, Riomet, Glucophage
• Drug: metformin (Arm B)
  rapamycin + metformin
  Other Name: Glumetza, Fortamet, Riomet, Glucophage
• Drug: rapamycin (Arm B)
  rapamycin + metformin
  Other Name: Sirolimus, Rapamune

Study Arms

• Experimental: A - metformin alone
  metformin alone Arm A patients will receive metformin 850mg orally twice a day on a 28 day cycle.
  Intervention: Drug: metformin alone (Arm A)
• Active Comparator: B - metformin + rapamycin
  metformin + rapamycin Arm B patients will receive 850mg orally twice a day and rapamycin 4mg orally once a day on a 28 day cycle.
  Interventions:

  • Drug: metformin (Arm B)
  • Drug: rapamycin (Arm B)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 27, 2014): 22
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: September 2019
• Actual Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma. Subjects with islet cell neoplasms are excluded.
• Have received 6 months of chemotherapy.
• Have stable disease for at least 6 months on the current regimen with the last 2 scans taken at least 6 months apart. Measurable disease not required.
• Eastern Cooperative Oncology Group performance status 0 or 1.
• Life expectancy of greater than 12 weeks.
• Adequate organ and marrow function.
• Oxygen saturation on room air > 92 % by pulse oximetry. (Subjects on intermittent or continuous supplemental oxygen are excluded).
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Receiving or has received any other investigational agents within 28 days prior to Day 1 of treatment in this study.
• Has undergone major surgery, other than diagnostic surgery (i.e. surgery done to obtain a biopsy for diagnosis or an aborted Whipple), within 28 days prior to Day 1 of treatment in this study.
• Known history of brain metastases unless previously treated and well controlled for at least 3 months (defined as stable clinically, no edema, no steroids).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or rapamycin.
• Taking ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin, rifampin, rifabutin, bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, protease inhibitors (e.g., HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir), metoclopramide, nicardipine, troleandomycin, verapamil, carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort (Hypericum perforatum), and grapefruit juice. Subjects on metformin will not be excluded.
• Has received any non-oncology live vaccine therapy used for prevention of infectious diseases for up to 28 days prior to or after the initiation of treatment in this study.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (bacterial, viral, or fungal infection(s) requiring systemic therapy), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Has serious medical risk factors involving any of the major organ systems such that the Investigator considers it unsafe for the subject to receive an experimental research drug.
• Unhealed surgical wound or other clinically significant wound.
• Known history of chronic HIV, Hepatitis B or hepatitis C infections.
• Pregnant or breast feeding.
• Unwilling or unable to comply with study procedures.
• Cannot reliably swallow pills.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02048384
• Other Study ID Numbers: J13146; NA_00090282 ( Other Identifier: JHMIRB )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Responsible Party: Same as current
• Current Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Study Sponsor: Same as current
• Collaborators: Stand Up To Cancer

Investigators

• Study Chair: Dung Le, MD; Johns Hopkins SKCCC

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: April 2021