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Clinical Trial of OPB-111077 in Patients With Relapsed or Refractory Acute Myeloid Leukaemia

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ClinicalTrials.gov Identifier: NCT03197714
Recruitment Status : Recruiting
First Posted : June 23, 2017
Last Update Posted : October 11, 2017
Sponsor:
Collaborators:
Otsuka Pharmaceutical Co., Ltd.
Apices Soluciones S.L.
Information provided by (Responsible Party):
Joaquín Martínez López, MD, PhD, Hospital Universitario 12 de Octubre

Brief Summary:

Phase Ib, open-label, dose-escalation clinical trial to evaluate the best-tolerated doses in Acute Myeloid Leukaemia (AML) relapsed or refractory to chemotherapy.

This open-label, nonrandomized trial will comprise 2 stages. A dose escalation stage will characterize the safety, tolerability and maximum tolerated dose (MTD), of OPB-111077.

Subsequently, an expansion stage will further evaluate the safety and antitumor activity of OPB-111077 in AML relapsed or refractory to chemotherapy.

Enrollment to the expansion cohort will begin following determination of the MTD.

Approximately 6-12 patients will be included in the phase I part of this clinical trial.

Additional patients will be included in the expansion cohort up to a total of 15 patients. The expansion cohort will serve to further evaluate safety simultaneously with preliminary efficacy.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: OPB-111077 Phase 1

Detailed Description:

The optimal management of relapsed AML in patients who are not candidates for HSCT has yet to be delineated. Given the median age at which AML is diagnosed and the high incidence of relapse and significant toxicities associated with standard intensive remission induction chemotherapy, new treatment options are needed to optimize AML outcomes. Changes on metabolism are critical in Acute Myeloid Leukaemia (AML); besides, leukemic cells have high requirements of energy and high basal metabolism. For this reason we hypothesized that deregulations of energy metabolism and mitochondria could play a central role in AML. OPB-111077, a novel low-molecular-weight compound discovered by Otsuka Pharmaceutical Co, Ltd, is a new class drug targeting cancer cell metabolisms and STAT3 and is being developed as an orally active antitumor agent for the treatment of various cancers. Sufficient preclinical studies have shown its activity in several types of tumors and especially in AML. Although in a phase I study their activity has been small in a group solid tumor, we may hypostatize that this drug could be more efficient in tumor cells with a high proliferative index as AML.

This is an open-label, phase Ib dose-escalation clinical trial to evaluate the safety and tolerability of oral OPB-111077 in AML relapsed or refractory to chemotherapy patients. OPB-111077 will be administered orally on a once daily dose schedule.

This open-label, nonrandomized trial will comprise 2 stages. A dose escalation stage will characterize the safety, tolerability and MTD, of OPB-111077. Subsequently, an expansion stage will further evaluate the safety and antitumor activity of OPB-111077 in AML relapsed or refractory to chemotherapy.

Enrollment to the expansion cohort will begin following determination of the MTD.

OPB-111077 recommended dose for expansion cohort will be defined during the phase I as MTD. Intra patient dose escalation is not allowed at any time of the study.

Patients will be included in the study upon signed informed consent and will follow study procedures.

Two dose schemas will be employed:

  • Level 1: 200 mg daily
  • Level 2: 250 mg daily The starting dose level of oral OPB-111077 will be 200 mg od. A 3 + 3 dose-escalation scheme will be used.

A minimum of 3 patients will be initially enrolled per cohort. DLTs will be assessed during the DLT assessment window of 28 days following the first dose of OPB-111077. Patients who withdraw or are withdrawn from the study prior to completing the DLT assessment window for reasons other than a DLT will not be considered evaluable for DLT and will be replaced.

DLTs will be assessed during the DLT assessment window of 28 days following the first dose of OPB-111077. Patients who withdraw or are withdrawn from the study prior to completing the DLT assessment window for reasons other than a DLT will not be considered evaluable for DLT and will be replaced.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Phase Ib, open-label, dose-escalation clinical trial to evaluate the best-tolerated doses in AML relapsed or refractory to chemotherapy
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib Clinical Trial of OPB-111077 in Patients With Relapsed or Refractory Acute Myeloid Leukaemia
Actual Study Start Date : September 7, 2017
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: OPB-111077
Level 1: 200 mg daily Level 2: 250 mg daily
Drug: OPB-111077

Two dose schemas will be employed:

  • Level 1: 200 mg daily
  • Level 2: 250 mg daily




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLT) of OPB-111077 in patients with in acute myeloid Leukemia. [ Time Frame: 28 days ]

    Any adverse event related to the study drug that occurred during the first cycle and considered relevant:

    • Any Grade 3 or 4 non-hematologic toxicity
    • Any unexpected non-tolerable grade II adverse event possibly related to the treatment regimen that requires delay beyond 1 week until recovery
    • Hematological toxicity is not considered doses limiting due to the characteristic of Acute Myeloid Leukemia.


Secondary Outcome Measures :
  1. Overall response rate. [ Time Frame: Up to 8 months ]
    Percentage of patients to reach complete remission (CR), morphologic complete remission with incomplete blood count recovery (Cri) or partial remission (PR) according to Cheson et al criteria.

  2. Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 8 months ]
    Number of events per patient according to NCI CTCAE vs 4.03

  3. Progression Free Survival [ Time Frame: Up to 8 months ]
    Time from the date of informed consent form to the date of progression or death (from any cause), whichever occurs first

  4. Overall Survival [ Time Frame: Up to 12 months ]
    Time from the date of informed consent form to the date of death due to any cause



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients at least 18 years old.
  • Patients diagnosed of non M3 acute myeloid leukemia in relapse after intensive chemotherapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  • Bilirubin ≤ 2 × Upper Limit of Normal (ULN). For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL.
  • Serum creatinine ≤2 × ULN or creatinine clearance (CrCl) ≥ 40 mL/min.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
  • Left Ventricular Ejection Fraction (LVEF) must be equal to or greater than 50%.
  • New York Heart Association (NYHA) congestive heart failure (CHF) class II or better.
  • Recovery from adverse effects of prior therapy at time of enrollment to ≤ Grade 1 (excluding alopecia).
  • Life expectancy ≥3 months
  • Patients, or appropriate designee, must be able to provide informed consent.

Exclusion Criteria:

  • Individuals with a history of other malignancies.
  • Subject has uncontrolled intercurrent illness that would limit compliance with study requirements.
  • Patients diagnosed of M3/Acute promyelocytic leukemia (APL).
  • The subject has received systemic antineoplastic therapy within 14 days of study treatment.
  • The subject has received any investigational agent within 28 days before the first dose of study treatment.
  • The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant Adverse Events (AEs).
  • The subject has concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment.
  • Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation.
  • Malabsorption syndrome.
  • Subject is unable to swallow capsules or tablets.
  • Subject is pregnant or breastfeeding.
  • Patients with history of allergic reactions attributed to components of OPB- 111077 that are not easily managed
  • Subject has systemic infection requiring IV antibiotic therapy within 7 days preceding the first dose of study drug, or other severe infection.
  • Uncontrolled intercurrent illness that would limit compliance with study requirements.
  • Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03197714


Contacts
Contact: Joaquín Martínez López, MD +34 917792787 jmartinezlo1967@gmail.com
Contact: Juan L Sanz Santos 918166804 ext 103 juanluis.sanz@apices.es

Locations
Spain
Hospital 12 Octubre Active, not recruiting
Madrid, Spain, 28041
Hospital Universitario La Fe Recruiting
Valencia, Spain, 46026
Contact: Pau Montesinos, MD    +34 96 1244000 ext 411966    montesinos_pau@gva.es   
Sponsors and Collaborators
Hospital Universitario 12 de Octubre
Otsuka Pharmaceutical Co., Ltd.
Apices Soluciones S.L.
Investigators
Principal Investigator: Joaquín Martínez López, MD Hospital 12 Octubre

Responsible Party: Joaquín Martínez López, MD, PhD, Head of Hematology Department, Hospital Universitario 12 de Octubre
ClinicalTrials.gov Identifier: NCT03197714     History of Changes
Other Study ID Numbers: FDO-LMA-2016-01
First Posted: June 23, 2017    Key Record Dates
Last Update Posted: October 11, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Joaquín Martínez López, MD, PhD, Hospital Universitario 12 de Octubre:
Myeloid Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms