Ridaforolimus in Treating Patients With Recurrent Metastatic and/or Locally Advanced Endometrial Cancer

A Phase II Study of Ridaforolimus in Patients With Metastatic And/Or Locally Advanced Recurrent Endometrial Cancer

RATIONALE: Ridaforolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase II trial is studying the side effects of ridaforolimus and to see how well it works in treating patients with recurrent metastatic and/or locally advanced endometrial cancer.

Study Overview

• Status: Completed
• Conditions: Endometrial Cancer
• Intervention / Treatment: Genetic: gene expression analysis; Other: laboratory biomarker analysis; Other: immunohistochemistry staining method; Drug: ridaforolimus

Detailed Description

OBJECTIVES:

• To assess the efficacy, in terms of objective response rate, of ridaforolimus, in patients with recurrent metastatic and/or locally advanced endometrial cancer.
• To assess the adverse events, time to progression, and response duration of this drug in these patients.
• To correlate objective tumor response with PTEN expression and other potential markers in primary tumor tissue from these patients.

OUTLINE: This is a multicenter study.

Patients receive oral ridaforolimus once daily on days 1-5 for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Archived tumor tissue samples (paraffin block or unstained slides) are analyzed for PTEN gene expression and other mTOR pathway elements to explore possible markers of response or non-progression by immunohistochemistry.

After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • BCCA - Cancer Centre for the Southern Interior
    • Surrey, British Columbia, Canada, V3V 1Z2
      • BCCA - Fraser Valley Cancer Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario at Kingston
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM - Hopital Notre-Dame
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University - Dept. Oncology
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed endometrial cancer, including any 1 of the following subtypes:

  • Adenocarcinoma

    • Papillary serous
    • Papillary
    • Villoglandular
    • Mucinous
    • Clear cell
  • Endometrioid
  • Adenosquamous carcinoma
• Recurrent or metastatic and/or locally advanced disease
• Incurable disease by standard therapies

• Clinically and/or radiologically documented disease within the past 28 days (35 days if negative), defined as ≥ 1 unidimensionally measurable disease site meeting 1 of the following criteria:

  • At least 20 mm by x-ray or physical exam
  • At least 10 mm by spiral CT scan
  • At least 20 mm by non-spiral CT scan
• Available tumor tissue (paraffin block or unstained slides) from primary tumor
• No uterine sarcoma (leiomyosarcoma), mixed müllerian tumor (MMT), and/or adenosarcoma

• No known brain metastases

  • Clinical suspicion of CNS involvement requires a head CT scan

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN
• Creatinine ≤ 1.25 times ULN OR creatinine clearance ≥ 50 mL/min
• Fasting serum cholesterol ≤ 9.0 mmol/L
• Fasting triglycerides ≤ 4.56 mmol/L
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Accessible for treatment and follow up (e.g., 1 ½ hours driving distance from participating center)
• No upper gastrointestinal or other condition that would impair swallowing or absorption of oral medication

• No serious illness or medical condition that would not permit the patient to be managed according to the protocol, including, but not limited to, any of the following:

  • History of significant neurologic or psychiatric disorder (e.g., uncontrolled psychotic disorders) that would impair the ability to obtain consent or limit compliance with study requirements
  • Active uncontrolled or serious infection
  • Active peptic ulcer disease
  • Myocardial infarction within the past 6 months, congestive heart failure (even if medically controlled), unstable angina, active cardiomyopathy, unstable ventricular arrhythmia, or uncontrolled hypertension
  • Pulmonary disease requiring oxygen
  • HIV infection or other immune deficiency
  • Other medical conditions that might be aggravated by study treatment
• No history of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
• No known hypersensitivity to the study drug or its components

PRIOR CONCURRENT THERAPY:

• At least 7 days since prior hormonal therapy (progestational or aromatase inhibitor) as either adjuvant therapy or for treatment of metastatic disease
• At least 21 days since prior major surgery and recovered

• At least 28 days since prior radiotherapy and recovered

  • Prior low-dose palliative radiotherapy allowed
• At least 4 months since prior adjuvant chemotherapy
• No prior mTOR inhibitors
• No prior or concurrent chemotherapy for metastatic or recurrent disease

• More than 7 days since prior and no concurrent CYP3A4 inhibitors including, but not limited to, any of the following:

  • Azole antifungals (i.e., ketoconazole, itraconazole, miconazole, fluconazole)
  • HIV protease inhibitors (i.e., indinavir, saquinavir, ritonavir, atazanavir, nelfinavir)
  • Clarithromycin
  • Verapamil
  • Erythromycin
  • Delavirdine
  • Diltiazem
  • Nefazodone
  • Telithromycin

• More than 12 days since prior and no concurrent CYP3A4 inducers including, but not limited to, any of the following:

  • Rifampin
  • Phenytoin
  • Rifabutin
  • St. John's wort
  • Carbamazepine
  • Efavirenz
  • Phenobarbital
  • Tipranavir
• At least 14 days since prior and no concurrent investigational drugs or anticancer therapy (e.g., immunotherapy, biological response modifiers [excluding hematopoietic growth factors], and systemic hormonal therapy)
• No concurrent CYP3A4 substrates

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ridaforolimus; oral ridaforolimus 40 mg days 1-5 each week (once daily for 5 consecutive days every week; cycle arbitrarily defined as a 4 week period)	Genetic: gene expression analysis; Other: laboratory biomarker analysis; Other: immunohistochemistry staining method; Drug: ridaforolimus; oral ridaforolimus 40 mg days 1-5 each week (once daily for 5 consecutive days every week; cycle arbitrarily defined as a 4 week period)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to progression		4 years
Objective response measured by RECIST criteria	After every second cycle	every 8 weeks
Adverse events	Adverse events will be monitored and assessed from the time of the first dose with overall results being assessed at final analysis.	4 years
Correlation between objective tumor response with PTEN expression and other potential markers	will be assessed overall at the time of completion of therapy and final analysis.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response duration	After progression with overall results assessed at final analysis	4 years

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Collaborators: Ariad Pharmaceuticals
• Investigators: Study Chair: Amit M. Oza, MD, Princess Margaret Hospital, Canada

Publications and helpful links

General Publications

• Tsoref D, Welch S, Lau S, Biagi J, Tonkin K, Martin LA, Ellard S, Ghatage P, Elit L, Mackay HJ, Allo G, Tsao MS, Kamel-Reid S, Eisenhauer EA, Oza AM. Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer. Gynecol Oncol. 2014 Nov;135(2):184-9. doi: 10.1016/j.ygyno.2014.06.033. Epub 2014 Aug 28.

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2008
• Primary Completion (Actual): March 19, 2012
• Study Completion (Actual): February 13, 2015

Study Registration Dates

• First Submitted: October 8, 2008
• First Submitted That Met QC Criteria: October 8, 2008
• First Posted (Estimated): October 9, 2008

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: stage IV endometrial carcinoma; recurrent endometrial carcinoma; stage III endometrial carcinoma; endometrial adenocarcinoma; endometrial adenosquamous cell carcinoma; endometrial clear cell carcinoma; endometrial papillary carcinoma
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Endometrial Neoplasms
• Other Study ID Numbers: I192; CAN-NCIC-IND192 (Registry Identifier: NCI US - Physician Data Query); ARIAD-CAN-NCIC-IND192 (Other Identifier: Ariad); CDR0000614597 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No