Clinical trial NCT00098891: MS-275 and Isotretinoin in Treating Patients With Metastatic or Advanced Solid Tumors or Lymphomas
Official title: A Phase I Study of an Oral Histone Deacetylase Inhibitor, MS-275 (NSC 706995, IND 61,198), in Combination With 13-Cis-Retinoic Acid in Metastatic Progressive Cancer.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Adult Grade III Lymphomatoid Granulomatosis
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-cell Lymphoma
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Intraocular Lymphoma
Nodal Marginal Zone B-cell Lymphoma
Primary Central Nervous System Non-Hodgkin 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 Mycosis Fungoides/Sezary Syndrome
Recurrent Small Lymphocytic Lymphoma
Small Intestine Lymphoma
Splenic Marginal Zone 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 Mycosis Fungoides/Sezary Syndrome
Stage IV Small Lymphocytic Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Waldenström Macroglobulinemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-12-09
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase I trial to study the effectiveness of combining MS-275 with isotretinoin in treating patients who have metastatic or advanced solid tumors or lymphomas. MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Isotretinoin may help cancer cells develop into normal cells. MS-275 may increase the effectiveness of isotretinoin by making cancer cells more sensitive to the drug. MS-275 and isotretinoin may also stop the growth of solid tumors or lymphomas by stopping blood flow to the cancer. Combining MS-275 with isotretinoin may kill more cancer cells

Detailed description: PRIMARY OBJECTIVES:

I. Determine the dose-limiting toxicity and maximum tolerated dose of MS-275 when administered with isotretinoin in patients with metastatic, progressive, refractory, or unresectable solid tumors or lymphomas.

SECONDARY OBJECTIVES:

I. Determine, preliminarily, tumor response in patients treated with this regimen.

II. Determine the pharmacokinetic profile of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation study of MS-275.

Patients receive oral MS-275 once on days 1, 8, and 15 and oral isotretinoin twice daily on days 1-21. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Cohorts of 3-6 patients receive escalating doses of MS-275 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 12 patients are treated at the MTD.

Patients are followed monthly.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed solid tumor or lymphoma

  * Metastatic, progressive, refractory, or unresectable disease
  * Not amenable to standard curative measures
* No known brain metastases
* Performance status - ECOG 0-2
* More than 3 months
* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* WBC ≥ 3,000/mm\^3
* Hemoglobin \> 9 g/dL
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST and ALT ≤ 2.5 times ULN
* No suspected Gilbert's syndrome
* Creatinine ≤ 1.5 times ULN
* Creatinine clearance ≥ 60 mL/min
* No symptomatic congestive heart failure
* No unstable angina pectoris
* No unstable cardiac arryhthmia
* Able to take and retain oral medications
* No malabsorption problems
* No acute or chronic gastrointestinal condition
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective double-method contraception 1 month before, during, and 3 months after study treatment
* No known HIV positivity
* No weight loss \> 10% within the past 2 months
* No history of allergic reaction attributed to compounds of similar chemical or biologic composition to MS-275 or isotretinoin
* No other uncontrolled illness
* No ongoing or active infection
* No seizure disorder
* No psychiatric illness or social situation that would preclude study participation
* More than 4 weeks since prior anticancer vaccine therapy
* More than 4 weeks since prior anticancer immunotherapy
* No concurrent anticancer vaccine therapy
* No concurrent anticancer immunotherapy
* More than 4 weeks since prior anticancer chemotherapy (6 weeks for nitrosoureas, mitomycin, or other agents known to cause prolonged marrow supression)
* No concurrent anticancer chemotherapy
* More than 4 weeks since prior anticancer hormonal therapy except gonadotropin-releasing hormone (GnRH) agonist therapy for non-castrated patients with prostate cancer
* Concurrent GnRH agonist therapy for non-castrated patients with prostate cancer allowed
* Concurrent luteinizing hormone-releasing hormone agonist therapy allowed provided there is evidence of tumor progression
* Concurrent adrenal steroid replacement therapy allowed
* No concurrent ketoconazole as second-line hormonal treatment for prostate cancer
* No concurrent corticosteroids except for treatment of refractory nausea or vomiting
* No other concurrent anticancer hormonal therapy
* More than 4 weeks since prior anticancer radiotherapy
* More than 2 weeks since prior palliative radiotherapy
* No concurrent anticancer radiotherapy
* More than 4 weeks since prior major surgery
* Recovered from all prior therapy
* No prior MS-275
* No prior oral isotretinoin

  * Isotretinoin for the treatment of acne allowed provided \> 3 years since prior administration
* More than 4 weeks since other prior anticancer therapy
* No concurrent tetracycline
* No concurrent high-dose vitamin A
* No concurrent valproic acid
* No other concurrent investigational agents
* No other concurrent anticancer therapy

Primary outcomes:
measure: Dose limiting toxicities defined as an adverse event which is likely related to the study medication
timeFrame: 28 days
measure: Maximum tolerated dose of entinostat and isotretinoin in combination
timeFrame: 28 days
Secondary outcomes:
measure: Pharmacokinetics
timeFrame: Up to day 21 of course 2
measure: Adverse events defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment
timeFrame: Up to 30 days after completion of study treatment
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Roberto Pili
role: PRINCIPAL_INVESTIGATOR
References: