A Phase 1 Dose Escalation Study of Tranylcypromine (TCP) in Combination With ATRA (Tretinoin) for Adult Patients With Relapsed/Refractory Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndromes (MDS)
Overview
- Phase
- Phase 1
- Intervention
- Tranylcypromine
- Conditions
- Acute Myelogenous Leukemia
- Sponsor
- University of Miami
- Enrollment
- 17
- Locations
- 1
- Primary Endpoint
- Rate of Toxicity in Study Participants Receiving TCP/ATRA Combination Therapy
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
Acute Myeloid Leukemia (AML) is a diverse disease that is fatal in the majority of patients. Acute promyelocytic leukemia (APL) however, a subtype of AML accounting for 5% of all cases, is very curable. APL cells are highly sensitive to the retinoid all-trans-retinoic acid (ATRA), which effectively differentiates the leukemic clone. Over 80% of APL patients can be cured with ATRA based therapies. For patients with non-APL AML, ATRA has little effect. Consequently, 85% of these patients will succumb to their disease despite conventional approaches. Little is known about mechanisms of resistance to ATRA in non-APL AML. This knowledge gap limits the use of ATRA in a disease that already has few effective therapies. The investigators' preliminary data suggest that non-APL AML cells can be re-sensitized to ATRA when combined with lysine-specific demethylase 1 (LSD 1) inhibitors. The investigators' publication in Nature Medicine showed that LSD1 inhibition with tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. Notably, treatment with ATRA and TCP markedly diminished the engraftment of primary human AML cells in murine models, indicating that the combination may target leukemia-initiating cells (LIC). The investigators' data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to ATRA resistance in non-APL AML. The investigators' central hypothesis is that ATRA combined with TCP will be safe and effective in a clinical population, and that this approach will suppress LICs and restore myeloid differentiation programs in patients with non-APL AML. Testing this hypothesis with the phase I clinical trial outlined in this protocol, will establish a new treatment paradigm in AML and extend the important anti-cancer effects of ATRA to all AML subtypes.
Investigators
Justin Watts, MD
Assistant Professor
University of Miami
Eligibility Criteria
Inclusion Criteria
- •Confirmed diagnosis of one of the following:
- •Relapsed/refractory Acute Myelogenous Leukemia (AML) as defined by the World Health Organization (WHO) criteria \[therapy-related AML and/or secondary AML from an antecedent hematologic disorder not excluded\].
- •Relapsed/refractory Myelodysplasic Syndrome (MDS) as defined by the World Health Organization (WHO) criteria.
- •Adult patients 18 years of age or older.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or
- •Adequate organ function as defined as:
- •Total bilirubin ≤ 1.5 x upper limited of normal (ULN)
- •ALT and AST must be ≤ 3 × ULN
- •Creatinine ≤ 1.5 x ULN or calculated creatinine clearance \> 50ml/min or
- •PT and aPTT ≤ 1.5 × ULN
Exclusion Criteria
- •Therapy with moderate or strong CYP3A4 inhibitors or CYP3A4 inducers within 14 days prior to Cycle1 Day
- •Therapy with Monoamine Oxidase Inhibitors (MAOIs), dibenzazepine derivatives, sympathomimetics, or Selective Serotonin Reuptake Inhibitors (SSRIs) within 14 days prior to Cycle1 Day
- •(Patients actively receiving a safe substitute in the judgment of the Principal Investigator are eligible and may continue to receive the safe substitute during protocol treatment)
- •Therapy with any investigational products, antineoplastic therapy, or radiotherapy within 14 days prior to Cycle1 Day
- •Patients actively receiving hydroxyurea are eligible and may continue to receive hydroxyurea during protocol treatment.
- •Candidates for standard and/or potentially curative treatments. (Candidate defined as a patient that is both eligible and willing)
- •Major surgery within 28 days prior to Cycle1 Day
- •Grade 2 or higher diarrhea as defined by NCI CTCAE Version 4.03 despite optimal antidiarrheal supportive care within 7 days prior to Cycle1, Day
- •Myocardial infarction within 6 months (24 weeks) prior to Cycle1, Day
- •Class III or IV heart failure as defined by the New York Heart Association (NYHA), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. (Any ECG abnormality at screening has to be documented by the investigator as not medically relevant and confirmed by the Principal Investigator)
Arms & Interventions
TCP Dose Level 1
20mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
Intervention: Tranylcypromine
TCP Dose Level 1
20mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
Intervention: Tretinoin
TCP Dose Level 2
40mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
Intervention: Tranylcypromine
TCP Dose Level 2
40mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
Intervention: Tretinoin
TCP Dose Level 3
60mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
Intervention: Tranylcypromine
TCP Dose Level 3
60mg of Tranylcypromine (TCP) to be administered orally twice a day (12 hours apart) for up to 16 cycles of 21 days each. 45 mg/m2 of Tretinoin (ATRA) to be administered orally twice a day (12 hours apart) beginning on day 4 of each 21 day cycle, for up to 16 cycles.
Intervention: Tretinoin
Outcomes
Primary Outcomes
Rate of Toxicity in Study Participants Receiving TCP/ATRA Combination Therapy
Time Frame: 24 months
The safety and tolerability of TCP/ATRA combination therapy in patients with Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndromes (MDS). This will be measured by the rate of adverse events, serious adverse events and other toxicities in study participants receiving protocol therapy.
Secondary Outcomes
- Pharmacokinetics (PK) effects of TCP in plasma when combined with ATRA(Baseline, Cycle 1, Cycle 2, 30 Days (+/-10 days) Post-End of Treatment)
- Pharmacodynamic (PD) effects of TCP in peripheral blood and bone marrow when combined with ATRA.(Baseline, Cycle 1, Cycle 2, 30 Days (+/-10 days) Post-End of Treatment)
- Rate of Preliminary Efficacy of TCP/ATRA Combination Therapy(24 months)