Clinical study investigating the safety PG545 in combination with nivolumab in patients with advanced solid tumours and in patients with metastatic pancreatic cancer

Phase 1

Completed

• Conditions: Advanced solid tumours; Pancreatic Cancer; Colorectal cancer; Cancer - Pancreatic; Cancer - Bowel - Back passage (rectum) or large bowel (colon)

• Registration Number: ACTRN12617001573347
• Lead Sponsor: Scientia Clinical Research Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-11-22
• Study Completion: 2020-10-27
• Last Update Posted: 21 June 2021

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

Stage 1
1. Histological or cytological documentation of non haematological, malignant solid tumour, excluding primary brain or spinal tumours.
2. Subjects with advanced solid tumours who have experienced failure of all standard therapies, no longer are candidates for standard therapy, have no standard therapy available, or choose not to pursue standard therapy (the latter is to be documented).
Stage 2:
PDAC arm 1. Histologically- or cytologically-proven metastatic adenocarcinoma of the pancreas.
PDAC arm 2. Patient’s acceptance to have a tumour biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator). The lesion to be biopsied cannot be used as a target lesion for RECIST assessment.
MSS mCRC arm 1. Histological documentation of metastatic (Stage IV) colorectal adenocarcinoma (mCRC).
MSS mCRC arm 2. Have confirmed microsatellite stable (MSS) mCRC; MSS is defined as 0-1 allelic shifts among 3-5 tumour microsatellite loci using a PCR-based assay or immunohistochemistry.
MSS mCRC arm 3. Patients must have progressed or been intolerant of at least two chemotherapy lines for metastatic disease. Patients who relapse within 6 months of adjuvant chemotherapy comprised of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one prior line of therapy.
MSS mCRC arm 4. Patient’s acceptance to have a tumour biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator). The lesion to be biopsied cannot be used as a target lesion for RECIST assessment.

General
3. Age 18 years and older.
4. Measurable disease (at least 1 target lesion) according to RECIST v1.1.
5. Life expectancy of at least 12 weeks.
6. ECOG Performance Status of 0 or 1.
7. Understand, sign and date informed consent to participate in study.
8. Able and willing to meet all protocol-required treatments, investigations and visits.
9. Have adequate organ function including: Bone Marrow Reserve: Absolute neutrophil count (ANC) not less than (NLT) 1500 cells/µL, platelets NLT 100,000/µL, haemoglobin N 9 g/dL; Hepatic: Bilirubin not more than (NMT) 1.5 x upper limits of normal (ULN), alanine transaminase (ALT) and aspartate transaminase (AST) NMT 2.5 x ULN (AST and ALT <5 times if liver metastases are present); Renal: > 60 mL/minute creatinine clearance (Cockroft and Gault equation); Coagulation: Activated partial thromboplastin time (APTT) NMT 1.2 x ULN and International Normalised Ratio (INR) NMT 1.4.
Update Key inclusion criteria

Exclusion Criteria

Stage 2:
PDAC 1. Subjects who have received more than one prior chemotherapy regimen.
General
MSS mCRC 1. High microsatellite instability (MSI-H) tumour
2. Clinically significant non-malignant disease including, but not limited to, hepatitis B or C, major surgery within 6 weeks of enrolment, active clinically significant infection, myocardial infarction within 6 months prior to enrolment, cerebrovascular event or transient ischaemic attack within 6 months prior to enrolment, or a condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents).
3. Clinically significant gastrointestinal bleeding within 4 weeks prior to enrolment or clinically-significant bleeding from the tumour within 4 weeks prior to enrolment.
4. Anti-cancer therapy within 4 weeks of Cycle 1 day 1 (excluding GnRH agonists for prostate cancer) or five times the half-life of the agent (if shorter).
5. Palliative radiation for bone metastases within 2 weeks of Cycle 1 day 1.
6. Active or prior CNS metastases.
7. Subjects who have received prior immune checkpoint targeting drugs (e.g., anti PD1, and PDL1, anti-KIR, anti CD137, etc)
8. Subjects with uncontrolled hypertension (defined as either resting systolic > 150 mmHg or resting diastolic > 100 mmHg; as measured at screening (average of three measurements).
9. History of allergy and/or hypersensitivity and/or other clinically significant adverse drug reaction to heparin or other anti-coagulant agents, or to any monoclonal antibody.
10. History of immune-mediated thrombocytopaenia or other platelet abnormalities or other hereditary or acquired coagulopathies, or laboratory evidence of anti-heparin antibodies, or any previous history of having tested positive for anti-heparin antibodies.
11. Use of heparin within two weeks prior to enrolment. Patients already receiving low molecular weight heparin (LMWH) compounds who have tested negative for anti-heparin antibodies at screening may be enrolled and continue LMWH therapy.
12. Patients on immunosuppressive agents except for systemic prednisone (or equivalent) of NMT 10 mg/day.
13. History of severe allergic, anaphylactic or other significant adverse reaction to radiographic contrast media (iodinated or non-iodinated), which cannot be managed by pre treatment with agents such anti histamines, and which, in the opinion of the Investigator, renders the subject unsuitable for routine CT or MRI scanning. Subjects who are contra-indicated for CT or MRI scanning for other reasons (e.g. ferromagnetic implants, profound claustrophobia), should not be enrolled.
14. Autoimmune disorders or any other pre-existing immunodeficiency condition (including known HIV infection).
15. Women who are pregnant or breast-feeding.
16. Women of child-bearing potential and male subjects who are partners of women of childbearing potential who are unable or unwilling to practice a highly effective means of contraception. Effective birth control includes: a) birth control pills, depot progesterone, or an intrauterine device plus one barrier method, or b) two barrier methods. Effective barrier methods are: male and female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). Women of child-bearing potential must practice a highly effective means of contraception for at least 5 months post last treatment; men for at least 7 months post last treatment.
17. Active substance abuse, including alcohol, which, in the opi

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Stage 1: Determine the maximum tolerated dose (MTD) of once-weekly intravenously administered PG545 in combination with intravenously administered nivolumab (240 mg every two weeks) in subjects with advanced solid tumours, as defined by dose limiting toxicity. The MTD is determined using dose limiting toxicities (DLTs) assessed by the treating physician, using NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. DLT toxicities also include the development of positive anti-heparin antibody, and an inability to complete the first dosing cycle due to any toxicity thought to be associated with the test drug.[28 days post treatment commencement.];Stage 2: To assess the safety and tolerability of weekly administration of PG545 in combination with nivolumab in patients with metastatic pancreatic cancer. Outcome is assessed by clinical examination and blood tests.[Weekly for the duration of the study.]