Advanced solid tumours Cancer
Conditions
Interventions
This is an open-label, sequential dose-escalation study in four parts: (1) dose escalation (Phase Ia), (2) additional monotherapy dose and cycle length assessments (Phase Ib (i) and (ii)) and fluorour
Sponsors
Starpharma (Australia)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed Informed Consent Form. 2. At least 18 years old. 3. Patients with histologically or cytologically confirmed advanced or metastatic cancer for which no standard therapy is available and who, in the opinion of the investigator, could potentially benefit from treatment with irinotecan or SN38-SPL9111. For monotherapy and 5-FU/LV combination therapy, preference will be given to patients with colorectal, pancreatic, ovarian, upper gastrointestinal, and breast cancers. Patients may also be irinotecan naïve. Exceptionally, tumours in other locations may be enrolled subject to sponsor approval. 4. Willing to be tested for uridine diphosphate-glucuronosyl transferase 1 family, polypeptide A1 (UGT1A1) genotype (if this result is not already available). 5. Willing to undergo testing for Dihydropyrimidine dehydrogenase (DPD) deficiency (if this result is not already available); only applicable to patients being considered for the combination treatment part of the study. 6. Measurable disease per RECIST version 1.1. 7. Adequate bone marrow reserve as demonstrated by an absolute neutrophil count (ANC) = 1.5 × 109/L or platelet count = 100 × 109/L (cannot be post-transfusion) or haemoglobin = 9 g/dL (can be post-transfusion). 8. Serum biliruin 1.5 ULN then calculated creatinine clearance must be 50 mL/min (using the Cockcroft-Gault formula). 11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 12. Life expectancy of greater than 12 weeks. 13. Reproductive inclusion criteria: 13.1. If of childbearing potential, willing to use an effective form of contraception (see below) during chemotherapy treatment and for at least six months thereafter. Such methods include (if using hormonal contraception this method must be supplemented with a barrier method, preferably male condom): 13.1.1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: 13.1.1.1. oral 13.1.1.2. intravaginal 13.1.1.3. transdermal 13.1.2. progestogen-only hormonal contraception associated with inhibition of ovulation: 13.1.2.1. oral 13.1.2.2. injectable 13.1.2.3. implantable 13.1.3. intrauterine device (IUD) 13.1.4. intrauterine hormone-releasing system (IUS) 13.1.5. bilateral tubal occlusion 13.1.6. vasectomised partner 13.1.7. true sexual abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. 13.2. Women must have a negative pregnancy test at study entry. 13.3. Men who are truly sexually abstinent when this is in line with the preferred and usual lifestyle of the subject or vasectomized or willing to ensure that their female sexual partners use a highly effective means of contraception (i.e. as outlined in Inclusion criterion 12.a.) for the duration of study therapy and 6 months afterwards. In addition, men must be willing to use a condom during sexual intercourse from the first dose of SN38-SPL9111 until 6 months after their final dose, to protect their partner from exposure to the study drug.
Exclusion criteria
Exclusion criteria: 1. Uncontrolled brain metastases or spinal cord compression. Patients who were treated with surgical resection or radiation therapy completing at least 4 weeks earlier are eligible if they are neurologically stable and have a follow-up Magnetic Resonance Imaging (MRI) scan performed within the previous 4 weeks showing no tumour progression. 2. Patients homozygous for the UGT1A1*28 allele (Gilbert syndrome) or patients with a congenital deficiency of UGT1A1 (Crigler-Najjar syndrome) will be excluded from the Phase I dose escalation/dose assessment parts of the study; they may be enrolled in the Phase II dose expansion parts starting at a reduced dose and incrementing to the full RD, if no excessive toxicity is encountered. 3. Patients with a Dihydropyrimidine dehydrogenase (DPD) deficiency identified by standard genotypic testing for the following gene variants: c. 1905+ 1G>A (rs3918290)DPYD*2A; c. 2846A>T (rs67376798); c.1679T>G (rs55886062)DYPD*13; c.1236G>A/HapB3DPYD (rs56038477); only applicable to patients considered for 5-FU/LV combination treatment. Patients identified as having one or more copies of these variants will be excluded from the combination treatment part of this study. Testing for DPD deficiency must be performed using a validated method which is recommended by local health authorities. 4. History of an untreated bleeding diathesis. 5. Active bowel obstruction, history of inflammatory bowel disease or chronic or acute gastrointestinal disorders with diarrhoea as a major symptom. 6. Allergy/hypersensitivity to irinotecan and SN38-containing preparations, pegylated drugs or other components of study therapy or compounds of similar chemical composition or, if enrolling for the 5-FU/LV combination therapy parts, components of 5-FU or LV or previous significant fluoropyrimidine toxicity. 7.1. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before screening 7.2. High cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year prior to screening 7.3. New York Heart Association (NYHA) Class III or IV congestive heart failure, unstable cardiac arrhythmias or uncontrolled blood pressure 7.4. Previous fluoropyrimidine-induced or associated cardiac toxicity; only applicable to patients considered for 5-FU/LV combination treatment. 8. Other uncontrolled intercurrent illness, including active infection. 9. Participation in a study of an investigational agent within 30 days prior to first dose of study therapy. 10. Anti-tumour therapy (including chemotherapy, radiation therapy, targeted therapeutics or hormonal therapy) within 28 days or 5-half-lives (whichever is shorter) prior to first dose of study therapy. Palliative radiotherapy will be permitted for non-target lesions provided it is completed 14 days prior to first dose of study drug. 11. Cumulative dose of corticosteroid = 150 mg prednisone (or equivalent doses of corticosteroids) within two weeks of the first IMP administration. 12. Unresolved toxicity from prior anti-tumour therapy, defined as toxicities (excluding alopecia) that have not resolved to < grade 2 or baseline as scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Exceptions may be allowed for stable toxicities after investigator discussion with the Medical Monitor and sponsor. 13. Major surgery within 28 days of first dose of study therapy. 14
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of SN38-SPL9111 assessed by monitoring safety through medical review of: 1. Adverse events (AEs) at all study visits; AEs will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 2. Physical examinations and electrocardiogram (ECG) at the screening visit, Day 1 of each dosing cycle, end of treatment visit and at Days 8 and 15 of Cycles 1 and 2, 3. Vital signs assessments at the screening visit, Day 1 of each dosing cycle, end of treatment visit and at Days 2,3, 4, 8 and 15 of Cycle 1 and Days 2,3,8 and 15 of Cycle 2 4. valuation of safety laboratory tests at the screening visit, Day 1 of each dosing cycle, end of treatment visit and at Days 2, 8 and 15 of Cycles 1 and 2 | — |
Secondary
| Measure | Time frame |
|---|---|
| Safety and Tolerability outcomes measured by: 1. Adverse events (AEs) at all study visits; AEs will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 2. Physical examinations and electrocardiogram (ECG) at the screening visit, Day 1 of each dosing cycle, end of treatment visit and at Days 8 and 15 of Cycles 1 and 2 3. Vital signs assessments at the screening visit, Day 1 of each dosing cycle, end of treatment visit and at Days 2,3, 4, 8 and 15 of Cycle 1 and Days 2,3,8 and 15 of Cycle 2 4. Evaluation of safety laboratory tests at the screening visit, Day 1 of each dosing cycle, end of treatment visit and at Days 2, 8 and 15 of Cycles 1 and 2 Preliminary efficacy outcomes: measured by computed tomography (CT) scan (with contrast unless contraindicated), magnetic resonance imaging (MRI) scans or applicable radiological assessment for patients of chest, abdomen and pelvis with additional anatomical areas based on the location of known and suspected metastases, as well as signs and symptoms of individual patients. For patients with neurological metastases, the primary imaging modality will be via MRI scans. Imaging scans will be assessed as per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 into the following categories: (1) complete response (CR); (2) partial response (PR); (3) stable disease; or (4) progressive disease. Scans will be performed at: • Baseline (within 28 days of first dose) • Every 9 weeks (+/- 7 days) from the first dose using the same method of assessment used at baseline. (b) Serum tumour markers applicable to the tumour type will be assayed and changes used to supplement the interpretation of the response. Tumour markers will be assayed at: • Screening and • Pre-dose at each cycle from Cycle 2 Pharmacokinetic outcomes will be measured by determination of the plasma concentrations of free SN38 and total SN38 (free SN38 and SN38-SPL9111) versus time by means of a v | — |
Countries
Australia, England, Scotland, United Kingdom
Contacts
Public ContactStephanie Edmondson
Outcome results
None listed