Oral Histone Deacetylase Inhibitor 4SC-202 in Patients With Advanced Hematologic Malignancies (TOPAS)

• ClinicalTrials.gov Identifier: NCT01344707
• Recruitment Status: Completed
• First Posted: April 29, 2011
• Last Update Posted: April 1, 2015
• Sponsor: 4SC AG
• Information provided by (Responsible Party): 4SC AG

Tracking Information

• First Submitted Date: April 12, 2011
• First Posted Date: April 29, 2011
• Last Update Posted Date: April 1, 2015
• Study Start Date: March 2011
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 29, 2013)

• Determination of Dose Limiting Toxicities of 4SC-202 [ Time Frame: 6 weeks ]
• Determination of Safety of 4SC-202 [ Time Frame: 6 weeks ]
  The safety and tolerability will be determined by occurrence of adverse events (AEs), vital signs (VS) [body temperature, weight, blood pressure (BP), pulse rate], electrocardiogram (ECG), performance status and clinical laboratory parameters.
• Determination of Pharmacokinetic Profile of 4SC-202 [ Time Frame: 3 weeks ]
  The plasma concentrations of 4SC-202 will be determined at the following time-points: Cycle 1 Day 1: Pre-dose, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 8 h, 24 h p.a. Cycle 1 Day 5: Pre-dose, 0.5 h, 1h, 2h Cycle 1 Day 14: Pre-dose, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 8 h, 24 h p.a. Cycle 2 Day 1: Pre-dose, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 8 h, 24 h p.a. using AUC0-infinity, AUClast, Cmax, tmax, t1/2, CL/F
• Determination of Maximum Tolerated Dose of 4SC-202 [ Time Frame: 6 weeks ]
• Determination of Tolerability of 4SC-202 [ Time Frame: 6 weeks ]
  The safety and tolerability will be determined by occurrence of adverse events (AEs), vital signs (VS) [body temperature, weight, blood pressure (BP), pulse rate], electrocardiogram (ECG), performance status and clinical laboratory parameters.

Original Primary Outcome Measures (submitted: April 28, 2011)

• Determination of Dose Limiting Toxicities of 4SC-202 [ Time Frame: 6 weeks ]
• Determination of Safety of 4SC-202 [ Time Frame: 6 weeks ]
  The safety and tolerability will be determined by occurance of adverse events (AEs), vital signs (VS) [body temperature, weight, blood pressure (BP), pulse rate], electrocardiogram (ECG), performance status and clinical laboratory parameters.
• Determination of Pharmacokinetic Profile of 4SC-202 [ Time Frame: 3 weeks ]
  The plasma concentrations of 4SC-202 will be determined at the following time-points: Cycle 1 Day 1: Pre-dose, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 8 h, 24 h p.a. Cycle 1 Day 5: Pre-dose Cycle 1 Day 14: Pre-dose, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 8 h, 24 h p.a. Cycle 2 Day 1: Pre-dose, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 8 h, 24 h p.a. using AUC0-24, AUC0-infinity, AUClast, Cmax, tmax, t1/2, CL/F
• Determination of Maximum Tolerated Dose of 4SC-202 [ Time Frame: 6 weeks ]
• Determination of Tolerability of 4SC-202 [ Time Frame: 6 weeks ]
  The safety and tolerability will be determined by occurance of adverse events (AEs), vital signs (VS) [body temperature, weight, blood pressure (BP), pulse rate], electrocardiogram (ECG), performance status and clinical laboratory parameters.

Current Secondary Outcome Measures (submitted: April 29, 2013)

• Assessment of potential anticancer activity of 4SC-202 [ Time Frame: 6 weeks ]
  The assessment will be performed by assessment of tumor response, duration of response and progression free survival
• Histone deacetylase (HADAC) inhibition in peripheral mononuclear cells [ Time Frame: 6 weeks ]
• Histone acetylation in peripheral mononuclear cells [ Time Frame: 6 weeks ]
• Gene expression analysis in peripheral blood [ Time Frame: 6 weeks ]
• Cytokine and miRNA levels in plasma [ Time Frame: 6 weeks ]

Original Secondary Outcome Measures (submitted: April 28, 2011)

• Assessment of potential anticancer activity of 4SC-202 [ Time Frame: 6 weeks ]
  The assessment will be performed by assessment of tumor response, duration of response and progression free survival
• Histone deacetylase (HADAC) inhibition in peripheral mononuclear cells [ Time Frame: 6 weeks ]
• Histone acetylation in peripheral mononuclear cells [ Time Frame: 6 weeks ]
• Gene expression analysis in peripheral blood [ Time Frame: 6 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Oral Histone Deacetylase Inhibitor 4SC-202 in Patients With Advanced Hematologic Malignancies (TOPAS)
• Official Title: Open Label, Dose Escalation Study of 4SC-202 in Patients With Advanced Hematologic Malignancies: First-In-Man Study of a Newly Developed, Oral Histone Deacetylase Inhibitor
• Brief Summary: The purpose of this study is to determine the Maximum Tolerated Dose, Dose Limiting Toxicities and optimal dosing schedule of 4SC-202 investigating its safety, tolerability and pharmacokinetics.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Hematologic Malignancies

Intervention

Drug: 4SC-202

oral administration dose escalation twice daily (bid)or three times a day (tid) continuous dosing for 21 days per cycle

• Study Arms: Not Provided
• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: April 28, 2011): 36
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: March 2015
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female patients, age ≥ 18 years.
• Patients with Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM),Myelodysplastic Syndrome (MDS) or malignant lymphoma which are relapsed and/or refractory to standard therapy or for which no standard therapy exists. Patients who are not eligible for curative stem cell transplantation or patients who have refused or are not eligible for frontline (chemo-) therapy may also be included.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2.
• Patients must have a live expectancy of 12 weeks or more.
• Patients must have adequate bone marrow reserve as well as adequate renal and hepatic function and serum electrolytes within a clinically acceptable range.
• Patients must have recovered from any treatment-related toxicities (to Grade 0 or 1 according to Common Terminology Criteria for Adverse Events (CTCAE); except for alopecia, fatigue and Grade 1 neurotoxicity) prior to registration.

Exclusion Criteria:

• Patients who have received previous treatment with an HDAC inhibitor.
• Patients with any gastrointestinal disorder that could interfere with the absorption of 4SC-202
• Patients who are unable to take oral medication.
• Patients with a history of other malignancies unless having undergone definitive treatment more than 5 years prior to entry into the study and without evidence of recurrent malignant disease, excluding patients with basal cell carcinoma of the skin; superficial carcinoma of the bladder; carcinoma of the prostate with a current prostate specific antigen (PSA) value of < 0.1 ng/ml; or cervical intraepithelial neoplasia.
• Patients with a history of, who were treated for, or who are suspected of having, hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Patients suspected of having any of these conditions should undergo appropriate evaluations prior to being enrolled in the study.
• Patients with precedent anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the last two weeks or a longer period depending on the known PK characteristics of the agents used.
• Patients with history or current evidence of clinically relevant allergies or idiosyncrasy to drugs (especially of similar chemical composition to the study drug) or food.
• Patients with symptomatic brain metastases/central nervous system (CNS) involvement.
• Patients with significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, congestive heart failure (New York Heart Association (NYHA) Class III or IV) related to primary cardiac disease, a condition requiring anti-arrhythmic therapy, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry.
• Patients with a marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval > 450 msec (Grade 1 CTCAE); Long-QT-Syndrome; the required use of concomitant medication on 4SC-202 dosing days that may cause Torsade de Pointes.
• Therapy with agents known to prolong the QT interval, such as certain antibiotics (i.e. erythromycin, clarithromycin), antidepressants (i.e. doxepin, amitryptilin) or neuroleptics (i.e. haloperidol, clozapin).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT01344707
• Other Study ID Numbers: 4SC-202-1-2010
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: 4SC AG
• Original Responsible Party: Same as current
• Current Study Sponsor: 4SC AG
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Andreas Engert, Prof. MD; Universitätsklinikum Köln

• PRS Account: 4SC AG
• Verification Date: January 2014