Ridaforolimus and Vorinostat in Treating Patients With Advanced Solid Tumors or Lymphoma
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1 |
Detailed Description
PRIMARY OBJECTIVES:
-
To determine which dose combinations of Ridaforolimus and Vorinostat are safe and tolerable.
-
To define the maximum tolerated dose. III. To characterize dose limiting toxicities.
SECONDARY OBJECTIVES:
-
To describe the activity of this combination amongst all enrolled patients in terms of response rate, progression free survival and overall survival.
-
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.
-
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 Design
Arms and Interventions
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. |
Drug: ridaforolimus
Given PO
Other Names:
Drug: vorinostat
Given PO
Other Names:
Procedure: biopsy
Optional correlative studies
Other Names:
Other: pharmacological study
Correlative studies
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) [First 3 weeks of treatment]
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.
Secondary Outcome Measures
- Progression Free Survival [1 year]
Kaplan Meier curves will be used. Proportions, 95% confidence intervals, and cumulative incidence curves will be used to characterize response rates.
- Overall Survival [1 year]
Kaplan Meier curves will be used. Proportions, 95% confidence intervals, and cumulative incidence curves will be used to characterize response rates.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Fox Chase Cancer Center | Rockledge | Pennsylvania | United States | 19046 |
Sponsors and Collaborators
- Fox Chase Cancer Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Elizabeth Plimack, Fox Chase Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 09-034
- NCI-2010-01907
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Treatment (Ridaforolimus and Vorinostat) |
---|---|
Arm/Group Description | 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. ridaforolimus: Given PO vorinostat: Given PO biopsy: Optional correlative studies pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies |
Period Title: Overall Study | |
STARTED | 16 |
COMPLETED | 15 |
NOT COMPLETED | 1 |
Baseline Characteristics
Arm/Group Title | Treatment (Ridaforolimus and Vorinostat) |
---|---|
Arm/Group Description | 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. ridaforolimus: Given PO vorinostat: Given PO biopsy: Optional correlative studies pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies |
Overall Participants | 15 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
5
33.3%
|
>=65 years |
10
66.7%
|
Age (years) [Median (Full Range) ] | |
Median (Full Range) [years] |
66
|
Sex: Female, Male (Count of Participants) | |
Female |
5
33.3%
|
Male |
10
66.7%
|
Region of Enrollment (participants) [Number] | |
United States |
15
100%
|
Outcome Measures
Title | Maximum Tolerated Dose (MTD) |
---|---|
Description | 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. |
Time Frame | First 3 weeks of treatment |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment (Ridaforolimus and Vorinostat) |
---|---|
Arm/Group Description | 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. ridaforolimus: Given PO vorinostat: Given PO biopsy: Optional correlative studies pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies |
Measure Participants | 15 |
Ridaforolimus qd days 1-5 every week |
20
|
Vorinostat bid days 1-3 every week |
100
|
Title | Progression Free Survival |
---|---|
Description | Kaplan Meier curves will be used. Proportions, 95% confidence intervals, and cumulative incidence curves will be used to characterize response rates. |
Time Frame | 1 year |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment (Ridaforolimus and Vorinostat) |
---|---|
Arm/Group Description | 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. ridaforolimus: Given PO vorinostat: Given PO biopsy: Optional correlative studies pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies |
Measure Participants | 15 |
Median (95% Confidence Interval) [weeks] |
17.1
|
Title | Overall Survival |
---|---|
Description | Kaplan Meier curves will be used. Proportions, 95% confidence intervals, and cumulative incidence curves will be used to characterize response rates. |
Time Frame | 1 year |
Outcome Measure Data
Analysis Population Description |
---|
Upper limit of confidence interval not reached because at least one patient was still alive at time of data cut-off. Upper limit given is amount of time (in weeks) of overall survival at data cut-off point. |
Arm/Group Title | Treatment (Ridaforolimus and Vorinostat) |
---|---|
Arm/Group Description | 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. ridaforolimus: Given PO vorinostat: Given PO biopsy: Optional correlative studies pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies |
Measure Participants | 15 |
Median (95% Confidence Interval) [weeks] |
40.7
|
Adverse Events
Time Frame | 162 weeks | |
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Treatment (Ridaforolimus and Vorinostat) | |
Arm/Group Description | 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. ridaforolimus: Given PO vorinostat: Given PO biopsy: Optional correlative studies pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies | |
All Cause Mortality |
||
Treatment (Ridaforolimus and Vorinostat) | ||
Affected / at Risk (%) | # Events | |
Total | 10/15 (66.7%) | |
Serious Adverse Events |
||
Treatment (Ridaforolimus and Vorinostat) | ||
Affected / at Risk (%) | # Events | |
Total | 0/15 (0%) | |
Other (Not Including Serious) Adverse Events |
||
Treatment (Ridaforolimus and Vorinostat) | ||
Affected / at Risk (%) | # Events | |
Total | 12/15 (80%) | |
Blood and lymphatic system disorders | ||
Thrombocytopenia | 11/15 (73.3%) | |
Anemia | 9/15 (60%) | |
Neutropenia | 4/15 (26.7%) | |
Gastrointestinal disorders | ||
Oral Mucositis | 12/15 (80%) | |
Diarrhea | 7/15 (46.7%) | |
Nausea | 6/15 (40%) | |
Constipation | 3/15 (20%) | |
General disorders | ||
Fatigue | 11/15 (73.3%) | |
Dysguesia | 5/15 (33.3%) | |
Investigations | ||
Elevated AST | 6/15 (40%) | |
Elevated ALT | 5/15 (33.3%) | |
Elevated Creatinine | 4/15 (26.7%) | |
Metabolism and nutrition disorders | ||
Anorexia | 11/15 (73.3%) | |
Hyperglycemia | 9/15 (60%) | |
weight loss | 6/15 (40%) | |
hypertriglyceridemia | 6/15 (40%) | |
Respiratory, thoracic and mediastinal disorders | ||
Pneumonitis | 3/15 (20%) | |
Skin and subcutaneous tissue disorders | ||
Rash, Maculo-Papular | 5/15 (33.3%) |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Elizabeth Plimack |
---|---|
Organization | Fox Chase Cancer Center |
Phone | 215-728-3889 |
Elizabeth.Plimack@fccc.edu |
- 09-034
- NCI-2010-01907