Ridaforolimus and Vorinostat in Treating Patients With Advanced Solid Tumors or Lymphoma

A Phase I Study of Ridaforolimus and Vorinostat in Patients With Advanced Solid Tumors or Lymphoma (IND 109130)

This phase I trial is studying the side effects and best dose of giving ridaforolimus and vorinostat together in treating patients with advanced solid tumors or lymphoma. Giving ridaforolimus in combination with vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: biopsy; Drug: vorinostat; Drug: ridaforolimus

Detailed Description

PRIMARY OBJECTIVES:

I. To determine which dose combinations of Ridaforolimus and Vorinostat are safe and tolerable.

II. To define the maximum tolerated dose. III. To characterize dose limiting toxicities.

SECONDARY OBJECTIVES:

I. To describe the activity of this combination amongst all enrolled patients in terms of response rate, progression free survival and overall survival.

II. To describe the activity of this combination in the subset of patients with RCC in terms of response rate, progression free survival and overall survival.

III. To describe the pharmacodynamic effects of these agents in combination.

OUTLINE: This is a dose escalation study.

Patients receive ridaforolimus orally (PO) once daily on days 1-5 and vorinostat PO twice daily on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every three months for up to 3 years.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Rockledge, Pennsylvania, United States, 19046
      • Fox Chase Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histological or cytological confirmation of a solid, malignant tumor or lymphoma that is refractory to standard therapies or for which no standard therapies exist
• Patients must have received at least one prior systemic therapy
• Measureable disease by RECIST v 1.1
• ECOG PS 0 or 1
• ANC >= 1500/uL
• Hgb >= 9 g/dL
• Platelets >= 100,000/uL
• AST/SGOT and ALT/SGPT =< 2.5 x upper limit of normal (ULN) or =< 5.0 x ULN in patients with liver metastases
• Total Bilirubin =< 1.5 times ULN
• Creatinine =< 2.0 mg/dL or Creatinine Clearance (calculated or 24 hour urine) >= 50 ml/min
• Female patients of childbearing potential must have a negative serum or urine pregnancy test =< 21 days of study enrollment and agree to use an effective method of contraception for the duration of the study
• Ability to understand and willingness to sign written informed consent

Exclusion Criteria:

• Prior anti-cancer treatment with either an mTOR inhibitor (i.e. temsirolimus, everolimus), or an HDAC inhibitor (i.e. Vorinostat)
• Patients who have received bevacizumab =< 6 weeks prior to day 1 of study treatment; patients who have received other chemotherapy, immunotherapy, or radiotherapy =< 3 weeks prior to day 1 of study treatment or those who have not recovered from acute adverse events due to agents administered >= 3 weeks earlier; for patients receiving targeted therapy, treatment must be discontinued at least five half-lives prior to initiation of day 1 of study treatment
• Patients who have taken valproic acid =< 2 weeks of study enrollment; valproic acid is another HDAC inhibitor
• Patients who are pregnant, plan to become pregnant, or are breastfeeding
• History of gastrointestinal bleeding within1 month of enrollment
• Serum cholesterol >= 350 mg/dL or serum triglycerides >= 400 mg/d
• Poorly controlled Type 1 or 2 diabetes, defined as hemoglobin A1C greater than 8% or a fasting glucose of > 160 mg/dL
• Active infection requiring antibiotics
• Anaphylactic reaction to macrolide antibiotics, Tween 80 (polysorbate 80)
• Patients who are not adequately recovered from a prior surgical procedure or major surgical procedure within 2 weeks prior to the first dose of study drug
• Myocardial infarction of unstable angina within 3 months of study entry
• NY Heart Association class III or IV congestive heart failure
• Known active parenchymal brain metastases; patients who have had brain metastases resected, or have received radiation therapy ending > 4 weeks prior to study entry are eligible if they meet all of the following criteria: 1) residual neurologic symptoms < grade 1, 2) no steroid requirement, 3) a follow-up MRI shows regression or stability of lesions after treatment, with no new lesions appearing
• Unable to swallow whole pills
• A requirement for one of the prohibited medications; if patient is currently taking one of these medications, they may be eligible so long as they discontinue the prohibited medication prior to starting study treatment and remain off for the duration they are taking study treatment
• Known diagnosis of HIV
• Concurrent malignancies are excluded with the following exceptions: basal cell skin cancer is allowed; cervical carcinoma in situ is allowed; any malignancy that does not require active treatment, and from which the patient has been disease free for >= 3 years is allowed

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: Treatment (ridaforolimus and vorinostat); Patients receive ridaforolimus PO once daily on days 1-5 and vorinostat PO twice daily on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Procedure: biopsy; Optional correlative studies; Other Names: biopsies; Drug: vorinostat; Given PO; Other Names: SAHA; Zolinza; L-001079038; suberoylanilide hydroxamic acid; Drug: ridaforolimus; Given PO; Other Names: deforolimus; AP23573; MK8669

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	MTD denoted as the highest dose at which no more than one of six patients experienced a dose limiting toxicity (DLT), and expanded to a total of 12 patients. Any drug-related grade 3 or 4 toxicity occurring during the first three weeks of treatment (except nausea, vomiting, diarrhea, serum lipid elevation, or transient electrolyte abnormality that resolved to a grade of 0-2 with medical management) was considered a dose limiting toxicity (DLT). Assessed by National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 4.0.	First 3 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Kaplan Meier curves will be used. Proportions, 95% confidence intervals, and cumulative incidence curves will be used to characterize response rates.	1 year
Overall Survival	Kaplan Meier curves will be used. Proportions, 95% confidence intervals, and cumulative incidence curves will be used to characterize response rates.	1 year

Collaborators and Investigators

• Sponsor: Fox Chase Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Elizabeth Plimack, Fox Chase Cancer Center

Publications and helpful links

General Publications

• Zibelman M, Wong YN, Devarajan K, Malizzia L, Corrigan A, Olszanski AJ, Denlinger CS, Roethke SK, Tetzlaff CH, Plimack ER. Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors. Invest New Drugs. 2015 Oct;33(5):1040-7. doi: 10.1007/s10637-015-0261-3. Epub 2015 Jun 20.

Helpful Links

• Related information

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: July 22, 2010
• First Submitted That Met QC Criteria: July 22, 2010
• First Posted (Estimate): July 26, 2010

Study Record Updates

• Last Update Posted (Actual): February 21, 2021
• Last Update Submitted That Met QC Criteria: February 2, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Vorinostat
• Other Study ID Numbers: 09-034 (Memorial Sloan-Kettering Cancer Center); NCI-2010-01907 (Registry Identifier: CTRP (Clinical Trials Reporting System))