Phase IIa Dose-Expansion and Biomarker Study of OPB-111077

Phase IIa Dose-Expansion and Biomarker Study of OPB-111077 in An Enriched Population of Treatment-Refractory Advanced Solid Tumors

This is a phase IIa open-label, non-randomized dose-expansion study of OPB-111077 in patients with advanced, treatment refractory cancers who have biopsy-amenable lesions at study entry.

Study Overview

• Status: Unknown
• Conditions: NPC; Refractory Tumor
• Intervention / Treatment: Drug: OPB-111077

Detailed Description

This is a phase IIa open-label, non-randomized dose-expansion study of OPB-111077 in patients with advanced, treatment refractory cancers who have biopsy-amenable lesions at study entry. Patients on the proposed study will be treated with the RPII dose of OPB-111077 (600mg on a 4 days-on, 3 days-off per week schedule). They will be enrolled in two parallel cohorts: i. patients with tumors predicted to be dependent on oxidative phosphorylation metabolism or oncogene addicted tumors which have developed resistance to primary TKI therapy, or ii. patients with nasopharyngeal carcinoma

Each cohort will contain 11-26 patients, over a period of 12-36 months. Subjects will receive OPB-111077 in 28-day cycles till disease progression or intolerable toxicity. Mandatory tumour biopsies will be performed at baseline and on cycle 1 day 15 (where feasible and accessible). Circulating biomarker blood sampling will be performed on days 1, 11 and 15 of cycle 1, and upon completion of OPB-111077 dosing. Pharmacokinetics blood sampling will be performed on days 11 and 15 of cycle 1. Safety assessments will be performed on cycle 1 day 1, cycle 1 day 8, cycle 1 day 15, bi-weekly till week 8, then monthly thereafter and response assessments will be performed every 8 weeks. Metabolic response assessment by PET/CT will be performed after 2 cycles of treatment, while radiologic response assessment will be performed after every 2 cycles of OPB-111077 from cycle 4 onwards.

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Andrea Wong, MBBS; Phone Number: (65) 6779 5555; Email: andrea_la_wong@nuhs.edu.sg
• Study Contact Backup: Name: Boon Cher Goh, MBBS; Phone Number: (65) 6779 5555; Email: phcgbc@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore, 119228
    • Recruiting
    • National University Hospital, Singapore
    • Contact: Andrea Wong, MBBS; Phone Number: +65 6772 4621; Email: Andrea_LA_Wong@nuhs.edu.sg
    • Sub-Investigator: Boon Cher Goh, MBBS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically confirmed, locally recurrent or metastatic solid tumors, who have failed standard treatment
2. Subjects with NPC will be eligible as long as they have received prior platinum therapy
3. Subjects with other types of solid tumors will be eligible if: i) their archival tumor sample shows over-expression oxidative phosphorylation markers e.g., PGC-1α/ SIRT1 or ii) they have oncogene-addicted cancers (e.g., EGFR mutation-positive NSCLC, EML4-ALK fusion NSCLC, BRAF-mutant melanomas, GIST, RET-driven thyroid cancers) which have become resistant to primary TKI therapy
4. All subjects must have at least one tumour lesion (primary or metastatic) that is suitable for free-hand or image-guided biopsy at baseline.
5. Age ≥ 21 years, Eastern Cooperative Oncology Group (ECOG) performance status < 1
6. Adequate bone marrow, liver and renal function
7. Baseline serum lactate ¬<3mmol/l
8. Capable of swallowing tablets
9. Recovery from any previous drug- or procedure-related toxicity to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 Grade 0 or 1 (except alopecia), or to baseline preceding the prior treatment.
10. Signed informed consent obtained before any study specific procedure. Subjects must be able to understand and be willing to sign the written informed consent.

Exclusion Criteria:

1. Chemotherapy, radiotherapy, surgery, immunotherapy or other therapy within 3 weeks of starting investigational medicinal product (IMP).
2. Use of any prohibited medications (CYP3A4 inhibitors and inducers) or medications which may predispose to lactic acidosis (e.g., metformin, nucleoside analogue reverse within 1 week prior to start of study drug administration
3. Pregnancy or breastfeeding.
4. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of study medication, and a negative result must be documented before start of study medication. Women of childbearing potential and men, must agree to use adequate contraception (barrier method of birth control) upon signing the informed consent form until at least 3 months after the last study drug administration.
5. Known or suspected allergy to the investigational agent or any agent given in association with this study.
6. Concurrent cancer which is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumours (Ta, Tis & T1) or any cancer curatively treated less than 3 years prior to study entry.
7. Interstitial lung disease with ongoing signs and symptoms at the time of screening.
8. Patients with CTCAE Grade 2 or higher peripheral neuropathy.
9. History of significant cardiac disease: congestive cardiac failure > NYHA class II, ongoing unstable angina, new-onset angina or myocardial infarction within the past 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Advanced refractory solid tumors; Patients with advanced refractory solid tumors will be enrolled.	Drug: OPB-111077; Receive 600 mg of OPB-111077 on a 4 days-on, 3 days-off per week in 28-day cycles till disease progression or intolerable toxicity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rates	This will be calculated as the percentage of evaluable patients achieving complete and partial response with OPB-111077 treatment, according to the RECIST 1.1 criteria	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolic response rates	This will be calculated as the percentage of evaluable patients achieving complete and partial metabolic response on 18F]-FDG PET/CT after 2 cycles of OPB-111077, as determined by the EORTC PET response criteria.	3 years
Progression free survival	This is defined as the time from the start of study treatment to documented progression of disease or death.	3 years
Haematologic and non-haematologic toxicities (all grades)	To evaluate the haematologic and non-haematologic toxicities of OPB-111077	3 years

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Otsuka Pharmaceutical Co., Ltd.

Publications and helpful links

General Publications

• Alam MM, Lal S, FitzGerald KE, Zhang L. A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors. Clin Transl Med. 2016 Mar;5(1):3. doi: 10.1186/s40169-016-0082-9. Epub 2016 Jan 26. Erratum In: Clin Transl Med. 2018 Mar 2;7(1):8.
• Vellinga TT, Borovski T, de Boer VC, Fatrai S, van Schelven S, Trumpi K, Verheem A, Snoeren N, Emmink BL, Koster J, Rinkes IH, Kranenburg O. SIRT1/PGC1alpha-Dependent Increase in Oxidative Phosphorylation Supports Chemotherapy Resistance of Colon Cancer. Clin Cancer Res. 2015 Jun 15;21(12):2870-9. doi: 10.1158/1078-0432.CCR-14-2290. Epub 2015 Mar 16.

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2017
• Primary Completion (Anticipated): May 22, 2020
• Study Completion (Anticipated): November 30, 2020

Study Registration Dates

• First Submitted: May 16, 2017
• First Submitted That Met QC Criteria: May 16, 2017
• First Posted (Actual): May 18, 2017

Study Record Updates

• Last Update Posted (Actual): June 15, 2017
• Last Update Submitted That Met QC Criteria: June 14, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Other Study ID Numbers: 2016/01181

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No