Clinical trial NCT01129193: AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma
Official title: Phase I Study of AR-42 in Relapsed Myeloma, Chronic Lymphocytic Leukemia, and Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Adult Nasal Type Extranodal NK/T-cell Lymphoma
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-cell Lymphoma
Cutaneous B-cell Non-Hodgkin Lymphoma
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Hepatosplenic T-cell Lymphoma
Intraocular Lymphoma
Nodal Marginal Zone B-cell Lymphoma
Peripheral T-cell Lymphoma
Post-transplant Lymphoproliferative Disorder
Prolymphocytic Leukemia
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
Refractory Chronic Lymphocytic Leukemia
Refractory Multiple Myeloma
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 Chronic Lymphocytic Leukemia
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 Multiple Myeloma
Stage III Mycosis Fungoides/Sezary Syndrome
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 Chronic Lymphocytic Leukemia
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
Testicular Lymphoma
Waldenstrom Macroglobulinemia
Lead sponsor: Ohio State University Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Arno Therapeutics
First posted: 2010-05-24
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: AR-42 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 AR-42 in treating patients with advanced or relapsed multiple myeloma, chronic lymphocytic leukemia, or lymphoma.

Detailed description: PRIMARY OBJECTIVES:

I. To estimate the safety by estimating the maximum tolerated dose (MTD) and describe the dose limiting toxicity (DLT) of AR-42 administered orally three times weekly (Mon, Wed, and Fri preferred) each week for 3 weeks during each 28-day period to adults with advanced or recurrent chronic lymphocytic leukemia (CLL), lymphoma, or multiple myeloma (MM).

SECONDARY OBJECTIVES:

I. To characterize the pharmacokinetics of AR-42 in this patient population. II. To analyze patient samples for descriptive information regarding AR-42 pharmacodynamic changes in this patient population.

III. To obtain pilot data regarding efficacy at the MTD as measured by partial and complete responses in each disease subgroup during protocol expansion in stage III.

OUTLINE:

Patients receive oral AR-42 three times weekly on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Eligibility criteria: Inclusion Hematologic Malignances Arm

* Patients must have CLL, prolymphocytic leukemia, or lymphoma (Hodgkins or Non-Hodgkins) as defined by 2008 WHO criteria or multiple myeloma as defined by IMWG criteria
* Patients must have received at least one prior antineoplastic therapy, must have progressed after at least 1 prior therapy, and for whom no standard therapy is available or whom decline such options; prior autologous and/or allogeneic transplant is permitted
* Prior biologic therapy or prior radiation is permitted; however, at least 28 days must have elapsed since the completion of prior therapy and patients must have recovered from all therapy-associated toxicities to no greater than grade 1 at the time of registration
* Patients with symptomatic disease may receive palliative corticosteroids up to 1 week before initiating therapy
* Patients must be off any prior chemotherapy for at least 28 days or 3 half lives, whichever is longer, and all therapy-related toxicity must have resolved to grade 1 or less
* ANC \>= 1000/uL
* Total bilirubin \< 1.5 mg/dL
* Serum creatinine =\< 1.5x institutional upper limit of normal or estimated creatinine clearance \>= 50 ml/min by MDRD (original or abbreviated), or measured creatinine clearance \>= 50 mL/min
* ECOG/WHO performance score of 0-1
* Patients must be able to swallow capsules
* Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial
* Women with potential for child bearing must have a negative pregnancy test at screening; both men and women are required to use appropriate contraception during study
* Platelet count \>= 50,000/uL
* AST and ALT =\< 5x the institutional upper limit of normal Inclusion Solid Tumors Arm
* Histologically or cytologically confirmed advanced or recurrent solid tumor malignancy.
* Chemotherapy: up to three prior cytotoxic chemotherapy treatments.
* Radiation Therapy: prior radiation therapy allowed.
* Surgery: Prior curative and palliative intent surgery is allowed.
* Age ≥ 18 years
* ECOG performance status 0-1
* Life expectancy of greater than 12 weeks.
* Patients must have normal organ and marrow function as defined below:
* Leukocytes ≥ 3,000/mcL
* Absolute neutrophil count ≥ 1,500/mcL
* Platelets ≥ 100,000/mcL
* Total bilirubin \< 1.5 mg/dL
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x institutional upper limit of normal (ULN); ≤ 5 x ULN in presence of liver metastasis
* Creatinine ≤ 1.5 x ULN OR Creatinine clearance ≥ 50 mL/min by MDRD (original or abbreviated), or measured creatinine clearance ≥ 50 ml/min
* Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial
* Women with potential for child bearing must have a negative pregnancy test at screening; both men and women are required to use appropriate contraception during study

Exclusion Hematologic Malignances Arm

* Pregnant women are excluded from this study
* Patients with malabsorption or any other condition that in the opinion of the principal investigator could cause difficulty in absorption of drug
* Breastfeeding should be discontinued if the mother is treated with AR-42
* Patients with malignant cells in the cerebrospinal fluid or parenchyma within the preceding 3 months or patients with primary CNS lymphoma are not eligible
* Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) are not eligible
* Patients receiving concurrent corticosteroids less than 1 week prior to protocol therapy other than for physiologic maintenance treatment or control of AIHA or ITP
* Concurrent use of complementary or alternative medicines that in the opinion of the principal investigator would confound the interpretation of toxicities and/or antitumor activity of the study drug
* Patients with a "currently active" second malignancy that, in the opinion of the principal investigator, will interfere with patient participation, increase patient risk, shorten survival to \< 1 year, or confound data interpretation
* Patients with a mean QTcB \> 450 msec in males and \> 470 msec in females
* Patients who are receiving concurrent antineoplastic therapy
* Any other medical condition, including mental illness or substance abuse, deemed by the principal investigator to likely interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
* Patients with significant cardiovascular disease, including a myocardial infarction or unstable angina within 6 months or unstable cardiac arrhythmias are not eligible for the study
* Known HIV infection

Exclusion Solid Tumors Arm

* Pregnant women are excluded from this study
* Patients with malabsorption or any other condition that in the opinion of the principal investigator could cause difficulty in absorption of drug
* Patients with malignant cells in the cerebrospinal fluid or parenchyma within the preceding 3 months or patients with primary CNS lymphoma are not eligible
* Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) are not eligible
* Patients receiving concurrent corticosteroids less than 1 week prior to protocol therapy other than for physiologic maintenance treatment or control of AIHA or ITP
* Concurrent use of complementary or alternative medicines that in the opinion of the principal investigator would confound the interpretation of toxicities and/or antitumor activity of the study drug
* Concurrent use of complementary or alternative medicines that in the opinion of the principal investigator would confound the interpretation of toxicities and/or antitumor activity of the study drug
* Patients with a "currently active" second malignancy that, in the opinion of the principal investigator, will interfere with patient participation, increase patient risk, shorten survival to \< 1 year, or confound data interpretation.
* Patients with a mean QTcB \> 450 msec in males and \> 470 msec in females
* Patients who are receiving concurrent antineoplastic therapy.
* Any other medical condition, including mental illness or substance abuse, deemed by the principal investigator to likely interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.
* Patients with significant cardiovascular disease, including a myocardial infarction or unstable angina within 6 months or unstable cardiac arrhythmias are not eligible for the study.

Primary outcomes:
measure: Adverse events described using the NCI CTCAE criteria
timeFrame: Up to 3 years
Secondary outcomes:
measure: Clinical benefit
timeFrame: Up to 3 years
measure: Duration of response
timeFrame: Up to 3 years
measure: Time to progression
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: The Ohio State University James Cancer Hospital
state: Ohio
Study officials:
affiliation: The Ohio State University James Cancer Hospital
name: Amir Mortazavi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Collier KA, Valencia H, Newton H, Hade EM, Sborov DW, Cavaliere R, Poi M, Phelps MA, Liva SG, Coss CC, Wang J, Khountham S, Monk P, Shapiro CL, Piekarz R, Hofmeister CC, Welling DB, Mortazavi A. A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies. Cancer Chemother Pharmacol. 2021 May;87(5):599-611. doi: 10.1007/s00280-020-04229-3. Epub 2021 Jan 25.
citation: Sborov DW, Canella A, Hade EM, Mo X, Khountham S, Wang J, Ni W, Poi M, Coss C, Liu Z, Phelps MA, Mortazavi A, Andritsos L, Baiocchi RA, Christian BA, Benson DM, Flynn J, Porcu P, Byrd JC, Pichiorri F, Hofmeister CC. A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas. Leuk Lymphoma. 2017 Oct;58(10):2310-2318. doi: 10.1080/10428194.2017.1298751. Epub 2017 Mar 7.
citation: Cheng H, Xie Z, Jones WP, Wei XT, Liu Z, Wang D, Kulp SK, Wang J, Coss CC, Chen CS, Marcucci G, Garzon R, Covey JM, Phelps MA, Chan KK. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents. AAPS J. 2016 May;18(3):737-45. doi: 10.1208/s12248-016-9876-3. Epub 2016 Mar 4.