Clinical trial NCT00659568: Metformin and Temsirolimus in Treating Patients With Metastatic or Unresectable Solid Tumor or Lymphoma
Official title: A Phase I Study of Temsirolimus in Combination With Metformin in Advanced Solid Tumours
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Endometrial Cancer
Kidney Cancer
Lung Cancer
Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: unspecified adult solid tumor, protocol specific
stage III renal cell cancer
stage IV renal cell cancer
recurrent renal cell cancer
recurrent endometrial carcinoma
stage III endometrial carcinoma
stage IV endometrial carcinoma
recurrent breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
recurrent small cell lung cancer
extensive stage small cell lung cancer
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult Hodgkin lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III adult T-cell leukemia/lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult Hodgkin lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV adult T-cell leukemia/lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult grade III lymphomatoid granulomatosis
recurrent adult Hodgkin lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult T-cell leukemia/lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
recurrent mycosis fungoides/Sezary syndrome
stage III mycosis fungoides/Sezary syndrome
stage IV mycosis fungoides/Sezary syndrome
adult nasal type extranodal NK/T-cell lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
Waldenström macroglobulinemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-04-16
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Metformin and temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of metformin when given together with temsirolimus in treating patients with metastatic or unresectable solid tumor or lymphoma.

Detailed description: OBJECTIVES:

Primary

* To establish the maximum tolerated dose and recommended phase II dose of metformin hydrochloride when administered with temsirolimus in patients with advanced solid cancers or lymphoma.

Secondary

* To determine the toxicity and safety, with particular reference to glucose and lipid deregulation, of this regimen in these patients.
* To assess antitumor activity, including tumor response rate and time to progression, in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of metformin hydrochloride.

Patients receive oral metformin once, twice, or three times daily on days 1-28 and temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed malignancy, including any of the following types:

  * Renal cell
  * Endometrial
  * Breast
  * Small cell lung carcinoma
  * Lymphoma
* Metastatic or unresectable disease for which standard curative or palliative measures do not exist or are no longer effective
* Measurable disease according to RECIST criteria
* No unstable primary CNS tumors or metastases

PATIENT CHARACTERISTICS:

Inclusion criteria:

* ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%
* Life expectancy \> 12 weeks
* Absolute neutrophil count ≥ 1.5 x 10\^9/L
* Platelets ≥ 100 x 10\^9/L
* AST ≤ 2.5 times upper limit of normal (ULN)
* Serum creatinine ≤ ULN
* Serum bilirubin ≤ 1.5 times ULN
* Negative pregnancy test
* Fertile patients must use effective contraception
* Able to understand and willing to sign a written informed consent document

Exclusion criteria:

* Allergies to or a history of allergic reactions attributed to any other compound of similar chemical or biologic composition to temsirolimus or metformin
* Diabetes mellitus (type I or II)
* Uncontrolled hypertriglyceridemia (triglyceride levels \> 10 mmol/L)
* History of lactic acidosis
* Inability to swallow or digest oral medications
* Uncontrolled intercurrent illness including, but not limited to, any of the following:

  * Uncontrolled hypertension
  * Ongoing or active infection
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
  * Psychiatric illness/social situation that would limit compliance with study requirements
* Significant traumatic injury within 21 days prior to treatment

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

* Recovered from all prior therapy
* At least 4 weeks since prior chemotherapy or radiotherapy (6 weeks for carmustine or mitomycin C) except low-dose, non-myelosuppressive radiotherapy
* No limitation on other prior therapy
* Concurrent low-dose anticoagulant (i.e., warfarin) allowed provided INR ≤ 1.1 times ULN
* Concurrent full-dose anticoagulant (i.e., warfarin) allowed provided INR is within institutional therapeutic range (usually 2.0-3.0)

Exclusion criteria:

* Major surgery within the past 21 days
* Prior temsirolimus (or other known inhibitors of mammalian target of rapamycin) or metformin
* Concurrent combination antiretroviral therapy for HIV-positive patients
* Concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) (e.g., phenytoin, carbamazepine, or phenobarbital) or other CYP3A4 inducer (e.g., rifampin or Hypericum perforatum \[St. John's wort\])
* Concurrent investigational or commercial agents or therapies to treat the patient's malignancy
* Other concurrent investigational agents other than temsirolimus or metformin

Primary outcomes:
measure: Maximum tolerated dose and recommended phase II dose of metformin hydrochloride when administered with temsirolimus
Secondary outcomes:
measure: Toxicity and safety, with particular reference to glucose and lipid deregulation
measure: Antitumor activity, including tumor response rate and time to progression
measure: Objective response
measure: Survival
measure: Frequency and severity of adverse events
Other outcomes:
Locations:
city: London
country: Canada
facility: London Regional Cancer Program at London Health Sciences Centre
state: Ontario
Study officials:
affiliation: London Health Sciences Centre
name: Mary Mackenzie, MD
role: PRINCIPAL_INVESTIGATOR
References: