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

Study Overview
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Brief Summary
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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.

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

Conditions
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Colorectal Cancer, Pancreatic Cancer, Gastric Cancers, Cholangiocarcinoma

Intervention / Treatment
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* Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Expansion)
* Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Escalation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be 18 years or older. Be male or non-pregnant females who agree to comply with applicable contraceptive requirements of the protocol (see Table 12. Acceptable Contraceptive Methods.) Histologically and/or cytologically confirmed gastrointestinal tumours that are metastatic or unresectable, and are subject to receive FOLFOX as SOC per investigator's judgement. Participants will have received at least one line of chemotherapy in the metastatic setting. Colorectal cancer: Patients must have received at least 1 prior line of therapy prior to enrollment in this study. Pancreatic cancer: Patients must have received at least 1 prior line of therapy. Gastric cancer: Patients who have not received prior treatment may be included in this study. GEJ (gastroesophageal junction) cancer patients are considered eligible to enter this trial. Cholangiocarcinoma: locally advanced or metastatic biliary tract cancer (intra or extrahepatic cholangiocarcinoma or gallbladder cancer) are eligible to enter this trial. Patients must have received at least 1 prior line of therapy (with gemcitabine-based chemotherapy). Colorectal cancer (ARM VI): Patients must have received at least 2 prior lines of therapy prior to enrollment in this study, one of which was a 5-FU based regimen. Have measurable disease according to RECIST v1.1 (at least one measurable lesion). Have an anticipated survival of at least 16 weeks. Be ambulatory, with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. Have adequate organ function, defined as: Hematologic: ANC ≥ 1.5 x 109/L, Hgb ≥ 9.0 g/dL and platelet count ≥ 100 x 109/L Hepatic: total bilirubin ≤ 1.5 x ULN (or ≤ 3 x ULN for subjects with Gilbert's Syndrome); transaminases ≤ 2.5 x ULN (may be up to ≤ 5x ULN if clearly due to liver metastases) and ALP ≤ 2.5 x ULN (or ≤ 3 x ULN if liver metastases). Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min. c. Urine protein is 0, trace, or +1 on dipstick urinalysis, or < 1.0 gram on 24-hour urine protein analysis Be on stable doses of any drugs that may affect hepatic drug metabolism or renal drug excretion (e.g., non-steroidal anti-inflammatory drugs, corticosteroids, barbiturates, diphenylhydantoin, narcotic analgesics, probenecid). Such drugs should not be initiated while the subject is participating in this study or have been initiated within 30 days beforehand before the start of treatment. Whenever possible, narcotic analgesic doses should be stable within 30 days prior to study entry and during the first cycle of therapy. Resolved acute effects of any prior therapy before the start of treatment to baseline severity or grade ≤1 CTCAE 5.0 except for adverse events not constituting a safety risk by investigator judgment (such as alopecia) Able to take oral medications (for pre-medications and supportive management) Understand and be able, willing, and likely to fully comply with study procedures and restrictions. Be fully informed about their illness and the investigational nature of the study protocol, and sign a REB-approved Informed Consent Form (ICF). 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 as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam. Any serious medical conditions that might be aggravated by treatment or limit compliance. This includes, but is not limited to uncontrolled psychiatric disorders, serious infections, active peptic ulcer disease and bleeding diathesis Any history of serious cardiac illness including (but not confined to): Previous or active myocardial infarction < 6 months before the start of treatment Congestive cardiac failure (NYHA III or IV) History of unstable angina pectoris < 6 months before the start of treatment Recent coronary artery bypass grafting < 6 months before the start of treatment Uncontrolled hypertension (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg) Ventricular arrhythmia < 6 months before the start of treatment Left ventricular ejection fraction (LVEF) < 50% as measured either by radionuclide angiography or echocardiogram QTc interval > 470 msec 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 (with the exception of non-melanoma skin cancer that had undergone curative treatment, cervical cancer in situ, or ductal/lobular carcinoma in situ of the breast that has underwent local 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. Current (within 1 week of the start of the study) or regular use of any medication (including OTC, herbal or homeopathic preparations) that could affect (improve or worsen) the cancer being studied, or could affect the action or disposition of BOLD-100, or its clinical or laboratory assessment, e.g., Coumadin therapy, due to high competitive protein binding. HIV-positive subjects on combination anti-retroviral therapy due to the potential for PK interactions with the study agent. Any condition potentially decreasing compliance to study procedures. Concurrent use of another investigational therapy or anti-cancer therapy. Concurrent use of another investigational therapy or anti-cancer therapy within 4 weeks before the start of treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part B - Dose Expansion - 1L Gastric Cancer (ARM I)<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Expansion)<br>* 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part B - Dose Expansion - 2L Gastric Cancer (ARM II)<br>Open to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Expansion)<br>* 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part B - Dose Expansion - 2L Pancreatic Cancer (ARM III)<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Expansion)<br>* 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part B - Dose Expansion - 2L Colorectal Cancer (ARM IV)<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Expansion)<br>* 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part B - Dose Expansion - 3L Colorectal Cancer (ARM VI)<br>Open to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Expansion)<br>* 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part B - Dose Expansion - 2L Cholangiocarcinoma (ARM V)<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Expansion)<br>* 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part A - Dose Escalation - Gastric Cancer<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Escalation)<br>* 320 mg/m2 IV over 30 minutes, q2weeks; 420 mg/m2 IV over 30 minutes, q2weeks; 500 mg/m2 IV over 30 minutes, q2weeks; 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part A - Dose Escalation - Pancreatic Cancer<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Escalation)<br>* 320 mg/m2 IV over 30 minutes, q2weeks; 420 mg/m2 IV over 30 minutes, q2weeks; 500 mg/m2 IV over 30 minutes, q2weeks; 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part A - Dose Escalation - Colorectal Cancer<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Escalation)<br>* 320 mg/m2 IV over 30 minutes, q2weeks; 420 mg/m2 IV over 30 minutes, q2weeks; 500 mg/m2 IV over 30 minutes, q2weeks; 625 mg/m2 IV over 30 minutes, q2weeks<br>|
| Experimental: Part A - Dose Escalation - Cholangiocarcinoma<br>Arm closed to enrollment. | Drug: BOLD-100 in combination with FOLFOX Chemotherapy (Dose Escalation)<br>* 320 mg/m2 IV over 30 minutes, q2weeks; 420 mg/m2 IV over 30 minutes, q2weeks; 500 mg/m2 IV over 30 minutes, q2weeks; 625 mg/m2 IV over 30 minutes, q2weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 |  | Screening to Study Discontinuation (an average of 2 months) | 
| Incidence of serious adverse events (SAE) and suspected unexpected serious adverse reactions; |  | Screening to Study Discontinuation (an average of 2 months) | 
| Incidence of dose-limiting toxicities (DLT) |  | Screening to Study Discontinuation (an average of 2 months) | 
| Incidence of clinically significant changes or abnormalities from Physical Examinations, ECGs, Vital Signs, Laboratory Results (chemistry, hematology, coagulation, urinalysis), Eastern Cooperative Oncology Group (ECOG) performance status |  | Screening to Study Discontinuation (an average of 2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS); Overall Response Rate (ORR); Overall Survival (OS) |  | Screening to Study Discontinuation (an average of 2 months) | 
| Standard PK parameters including Cmin |  | Screening to Study Discontinuation (an average of 2 months) | 
| Baseline GRP78 biomarker levels (Counts/mL) |  | Baseline | 
| Changes in GRP78 biomarker levels during treatment (Counts/mL) |  | Screening to Study Discontinuation (an average of 2 months) | 
| Standard PK parameters including Cmax |  | Screening to Study Discontinuation (an average of 2 months) | 
| Standard PK parameters including TSS |  | Screening to Study Discontinuation (an average of 2 months) | 
| Standard PK parameters including CSS |  | Screening to Study Discontinuation (an average of 2 months) | 
| Standard PK parameters including Vdss |  | Screening to Study Discontinuation (an average of 2 months) |