BOLD-100 in Combination With FOLFOX for the Treatment of Advanced Solid Tumours

Official title

A Phase 1b/2a Dose Escalation Study of BOLD-100 in Combination With FOLFOX Chemotherapy in Patients With Advanced Solid Tumours

Overview

BOLD-100 is an intravenously administered sterile solution containing the ruthenium-based small molecule. BOLD-100 has been shown to preferentially decrease the expression of GRP78 in tumour cells and ER stressed cells when compared to normal cells. BOLD-100 will be combined with cytotoxic FOLFOX chemotherapy in this study, with a dose escalation cohort to ensure tolerability and safety, followed by a cohort expansion phase.

Detailed description

BOLD-100 is a novel, targeted anti-cancer therapy which is an intravenously administered small molecule drug. In a previous Phase 1 study (NCT01415297) BOLD-100 showed low toxicity with minimal hematological issues as well as some potential anti-tumour activity. The lack of observed hematological toxicity and neurotoxicity position BOLD-100 well for use in combination with a broad range of standard-of-care (SOC) chemotherapy regimens.

This is a prospective, multicenter non-randomized Phase 1b/2a dose escalation \& expanded cohort study of BOLD-100 in patients with advanced gastrointestinal malignancies (colorectal, pancreatic, gastric cancers, and cholangiocarcinoma) receiving standard-of-care FOLFOX chemotherapy. Enrollment in Arms I - VI is closed to enrollment.

Colorectal cancer (ARM VII) for patients who are oxaliplatin naïve and have received only 1 prior line of therapy in the metastatic setting. Within this arm, participants will be randomized to one of two dose levels of BOLD-100 - either 500 mg/m2 or 625 mg/m2 in combination with FOLFOX or FOLFOX alone, in a 1:1:1 ratio. Participants enrolled into Arm VII will complete quality of life questionnaires examining general quality of life and neuropathy associated quality of life parameters.

Interventions

• Drug BOLD-100 +/- FOLFOX Chemotherapy (Arm VII)
  Arm VIIA: 500 mg/m2 BOLD-100 combined with FOLFOX; Arm VIIB: 625 mg/m2 BOLD-100 combined with FOLFOX; Arm VIIC: FOLFOX alone
• Drug BOLD-100 in combination with FOLFOX Chemotherapy (Arms I-VI)
  BOLD-100 at 625 mg/m2 combined with FOLFOX Chemotherapy

Primary outcome measures

• Incidence and severity of adverse events ([S]AEs) [Time frame: Through study completion, approximately 2 weeks after last treatment]
• Incidence of dose-limiting toxicities (DLT) [Time frame: Screening to 4 weeks after first treatment]
• Incidence of clinically significant changes or abnormalities from Physical Examinations, ECGs, Vital Signs, Laboratory Results, ECOG performance status [Time frame: Through study completion, approximately 2 weeks after last treatment]
• Progression Free Survival (PFS): Arm VII [Time frame: Through study completion, approximately 2 weeks after last treatment for last patient]
• Overall Response Rate (ORR): Arm VII [Time frame: Through study completion, approximately 2 weeks after last treatment for last patient]
• Overall Survival (OS): Arm VII [Time frame: Through study completion, approximately 2 weeks after last treatment for last patient]

Secondary outcome measures (7)

• Progression Free Survival (PFS): Arms I-VI [Time frame: Through study completion, approximately 2 weeks after last treatment for last patient]
• Overall Response Rate (ORR): Arms I-VI [Time frame: Through study completion, approximately 2 weeks after last treatment for last patient]
• Overall Survival (OS): Arms I-VI [Time frame: Through study completion, approximately 2 weeks after last treatment for last patient]
• Baseline and changes in biomarker levels during treatment [Time frame: Arms I-VII; Through study completion, approximately 2 weeks after last treatment]
• Peak Plasma Concentrations (Cmax) [Time frame: Arms I-VII; Through study completion, approximately 2 weeks after last treatment]
• Area under the plasma concentration versus time (AUC) [Time frame: Arms I-VII; Through study completion, approximately 2 weeks after last treatment]
• Elimination half life (T1/2) [Time frame: Arms I-VII; Through study completion, approximately 2 weeks after last treatment]

Eligibility criteria

Inclusion criteria

• Be 18 years or older.
• Be male or non-pregnant females who agree to comply with applicable contraceptive requirements of the protocol.
• Histologically and/or cytologically confirmed gastrointestinal tumours that are metastatic or unresectable. (ARM VII): Patients must have received only 1 prior line of therapy in the metastatic setting.
• Have measurable disease according to RECIST v1.1.
• Have an anticipated survival of at least 16 weeks.
• Be ambulatory, with an ECOG performance score of 0 or 1.
• Have adequate organ function.
• Be on stable doses of any drugs that may affect hepatic drug metabolism or renal drug excretion.
• Be fully informed about their illness and the investigational nature of the study protocol, and sign a REB-approved Informed Consent Form (ICF).
• (ARM VII): BRAF wild-type tumour status.

Exclusion criteria

• Neuropathy > grade 2
• Previous intolerance to or significant reaction secondary to fluorouracil or oxaliplatin.
• Cerebrovascular accident within the past 6 months before the start of treatment.
• History or presence of central nervous system (CNS) metastasis or leptomeningeal tumours.
• Any serious medical conditions that might be aggravated by treatment or limit compliance.
• Any history of serious cardiac illness.
• Hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months before the start of treatment.
• Any other known malignancy within 3 years before the start of treatment.
• Active gastrointestinal tract disease with malabsorption syndrome.
• Non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease.
• Treatment with radiation therapy or surgery within 4 weeks prior to starting treatment.
• Recent history of weight loss > 10% of current body weight in past 3 months before the start of treatment.
• HIV-positive subjects on combination anti-retroviral therapy due to the potential for PK interactions with the study agent.
• Concurrent use of another investigational therapy or anti-cancer therapy within 4 weeks before the start of treatment.
• Currently breastfeeding
• Dihydropyrimidine Dehydrogenase (DPD) deficiency
• Current or prior treatment with potent inhibitors of Dihydropyrimidine Dehydrogenase (DPD)
• (ARM VII): Prior exposure to BOLD-100
• (ARM VII): Subjects with microsatellite-high (MSI-H) Tumours
• (ARM VII): Concurrent monoclonal antibody therapy for mCRC (anti-EGFR, anti-VEGF or anti-HER2)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 6 centers

• Cross Cancer Institue — Edmonton
• Juravinski Cancer Centre — Hamilton
• The Ottawa Hospital Cancer Centre — Ottawa
• Princess Margaret Cancer Centre — Toronto
• Jewish General Hospital — Montreal
• McGill University Health Centre Glen Site — Montreal

South Korea · 5 centers

• National Cancer Center — Goyang
• Kangbuk Samsung Hospital — Seoul
• Samsung Medical Center — Seoul
• Seoul National University Hospital — Seoul
• Severance Hospital - Yonsei University — Seoul

Ireland · 3 centers

• Mater Miserecordiae University Hospital — Dublin
• St. James Hospital — Dublin
• St. Vincent's University Hospital — Dublin

Italy · 3 centers

• Fondazione IRCCS "Istituto Nazionale dei Tumori — Milan
• AOU L. Vanvitelli — Naples
• Azienda Ospedaliero Universitaria Pisana — Pisa

Spain · 3 centers

• Vall Hebron Institute of Oncology (VHIO) — Barcelona
• Early Phase Unit FJD START Madrid — Madrid
• Hospital 12 de Octubre — Madrid

United States · 2 centers

• University of California, Los Angeles — Santa Monica
• Moffitt Cancer Center — Tampa

Germany · 2 centers

• Universitatsklinikum Bonn — Bonn
• University Hospital of Ulm — Ulm

Identifiers

NCT: NCT04421820 · BOLD-100-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗