None listed
Conditions
Brief summary
This study will determine the safety and tolerability of PG545 in combination with Nivolumab in patients with advanced solid tumours or metastatic pancreatic cancer. Who is it for? You may be eligible to join this study if you are aged 18 years old or above and have a non- haematological, malignant solid tumour (for Stage 1) or metastatic adenocarcinoma of the pancreas (for Stage 2). Study details This study has two stages: Stage 1 to establish the maximum tolerated weekly dose of PG545 intravenous (IV) infusion in combination with fortnightly Nivolumab IV infusion, and stage 2 to safety and tolerability of the recommended dose from stage 1 of PG545 IV infusion in combination with fortnightly Nivolumab IV infusion. Treatment in both stages will continue until disease progression, unacceptable toxicity or participant withdrawal. Participants will be regularly assessed throughout the study in order to monitor safety and tumour response. It is envisaged that the combination of PG545 and Nivolumab will improve on the limited treatment options currently available for patients with pancreas cancer. Once demonstrated to be safe, the combination can then be explored in larger clinical studies in pancreas cancer and other tumour types.
Interventions
Stage 1: Dose escalation in patients with advanced or metastatic solid tumours: PG545 25, 50 or 100 mg once weekly via IV infusion and Nivolumab 240 mg every two weeks via IV infusion. Patients receive weekly doses of PG545 according to the cohort to which they are assigned. A standard 3+3 cohort design is employed for each cohort. Intrasubject escalation to the next highest dose is allowed once the next highest dose has been demonstrated to be tolerated.
Stage 2: Expansion phase in patients wit
Stage 1: Dose escalation in patients with advanced or metastatic solid tumours: PG545 25, 50 or 100 mg once weekly via IV infusion and Nivolumab 240 mg every two weeks via IV infusion. Patients receive weekly doses of PG545 according to the cohort to which they are assigned. A standard 3+3 cohort design is employed for each cohort. Intrasubject escalation to the next highest dose is allowed once the next highest dose has been demonstrated to be tolerated. Stage 2: Expansion phase in patients with metastatic pancreas tumour or MSS mCRC: Recommended PG545 dose from Stage 1 once weekly via IV infusion and Nivolumab 240 mg every two weeks via IV infusion. Treatment to continue until disease progression or withdrawal due to tolerability. Patients will be treated at site ensuring treatment compliance.
Sponsors
Scientia Clinical Research Limited
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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 opinion of the Investigator, risks impairing the ability of the subject to comply with the protocol. 18. Subjects who have received an investigational agent within 28 days prior to Cycle 1 Day 1 or five times the half-life of the investigational agent (if shorter); or are currently participating in any other clinical study or research project which involves administration of a pharmaceutical product or experimental treatment, or which involves protocol-specified laboratory tests, imaging studies or other investigations.
Outcome results
None listed