| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | Colorectal Cancer
Pancreatic Cancer
Gastric Cancers
Cholangiocarcinoma | |
| E.1.1.1 | Medical condition in easily understood language | | Advanced solid gastrointestinal tumours | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10052362 | | E.1.2 | Term | Metastatic colorectal cancer | | E.1.2 | System Organ Class | 100000004864 | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10033605 | | E.1.2 | Term | Pancreatic cancer metastatic | | E.1.2 | System Organ Class | 100000004864 | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10017770 | | E.1.2 | Term | Gastric carcinoma | | E.1.2 | System Organ Class | 100000004864 | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10077846 | | E.1.2 | Term | Cholangiocarcinoma metastatic | | E.1.2 | System Organ Class | 100000004864 | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | PART A (DOSE ESCALATION):
To assess the safety, tolerability and Maximum Tolerated Dose (MTD) of FOLFOX standard-of-care (FOLFOX SOC) combination chemotherapy + BOLD-100 in advanced solid tumours.
PART B (DOSE EXPANSION PHASE):
1. To assess response rates to SOC combination chemotherapy + BOLD-100 in advanced solid tumours | |
| E.2.2 | Secondary objectives of the trial | PART A:
1. To assess response rates to SOC combination chemotherapy + BOLD-100 in advanced solid tumours.
2. To evaluate the pharmacokinetic and pharmacodynamic parameters of BOLD-100.
3. To assess potential biomarkers (GRP78) predictive of efficacy.
PART B:
1. To assess the safety, tolerability & MTD of SOC combination chemotherapy + BOLD-100 in advanced solid tumours.
2. To evaluate the pharmacokinetic and pharmacodynamic parameters of BOLD-100.
3. To assess potential biomarkers (GRP78) predictive of efficacy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Be 18 years or older.
2. Be male or non-pregnant females who agree to comply with applicable contraceptive requirements of the protocol.
3. Histologically and/or cytologically confirmed gastrointestinal tumours that are metastatic or unresectable, and have received at least one line of chemotherapy in the metastatic setting (in the dose escalation phase only). For the dose expansion phase, the setting will vary based on the malignancy. 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. Cholangiocarcinoma: Patients must have received at least 1 prior line of therapy (with gemcitabine-based chemotherapy).
4. Have measurable disease according to RECIST v1.1 (at least one measurable lesion).
5. Have an anticipated survival of at least 16 weeks.
6. Be ambulatory, with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
7. 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; transaminases ≤ 2.5 x ULN (may be up to 5 x ULN if clearly due to liver metastases), ALP ≤ 2.5 x ULN
- Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min.
- Urine protein is 0, trace, or +1 on dipstick urinalysis, or < 1.0 gram on 24-hour urine protein analysis
8. 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. Whenever possible, narcotic analgesic doses should be stable within 30 days prior to study entry and during the first cycle of therapy.
9. Resolved acute effects of any prior therapy to baseline severity or grade ≤1 CTCAE 5.0 except for adverse events not constituting a safety risk by investigator judgment (such as alopecia).
10. Able to take oral medications (for pre-medications and supportive management).
11. Understand and be able, willing, and likely to fully comply with study procedures and restrictions.
12. Be fully informed about their illness and the investigational nature of the study protocol, and sign an approved Informed Consent Form (ICF).
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| E.4 | Principal exclusion criteria | 1. Neuropathy > grade 2.
2. Previous intolerance to or significant reaction secondary to fluorouracil or oxaliplatin.
3. Cerebrovascular accident within the past 6 months.
4. 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.
5. 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.
6. Any history of serious cardiac illness including (but not confined to):
o Previous or active myocardial infarction < 6 months
o Congestive cardiac failure (NYHA III or IV)
o History of unstable angina pectoris < 6 months
o Recent coronary artery bypass grafting < 6 months
o Uncontrolled hypertension (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg)
o Ventricular arrhythmia < 6 months
o Left ventricular ejection fraction (LVEF) < 50% as measured either by radionuclide angiography or echocardiogram
o QTc interval > 470 msec
7. Hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months
8. Any other known malignancy within 3 years (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.
9. Active gastrointestinal tract disease with malabsorption syndrome.
10. Non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease.
11. Treatment with radiation therapy or surgery within one month prior to study entry.
12. Recent history of weight loss > 10% of current body weight in past 3 months.
13. 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. Subjects taking ANY supplemental IRON, i.e., therapeutic or as part of a multivitamin regimen, are excluded from this study, whether prescribed or self-medicated.
14. HIV-positive subjects on combination anti-retroviral therapy due to the potential for PK interactions with the study agent.
15. Any condition potentially decreasing compliance to study procedures.
16. Concurrent use of another investigational therapy or anti-cancer therapy.
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| E.5 End points |
| E.5.1 | Primary end point(s) | 1. Incidence and severity of adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
2. Incidence of serious adverse events (SAE) and suspected unexpected serious adverse reactions.
3. Incidence of dose-limiting toxicities (DLT).
4. 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. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | An average of 2 months for all primary end-points listed. | |
| E.5.2 | Secondary end point(s) | 1. Progression Free Survival (PFS); Overall Response Rate (ORR); Overall Survival (OS).
2. Standard PK parameters including Cmin.
3. Baseline GRP78 biomarker levels (Counts/mL).
4. Changes in GRP78 biomarker levels during treatment (Counts/mL).
5. Standard PK parameters including Cmax.
6. Standard PK parameters including TSS.
7. Standard PK parameters including CSS.
8. Standard PK parameters including Vdss.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point | | An average of 2 months for all secondary end-points listed, except for the baseline GRP78 biomarker levels (this is done at baseline). | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description | | Phase 1b/2a trial conducted in 2 parts (Part A is dose escalation; Part B is expansion phase) | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Canada | | Ireland | | Korea, Republic of | | United States | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
