GINISORTAMAB for Metastatic pancreatic ductal adenocarcinoma

Inclusion criteria

• {"criterion_text":"- For all trial participants: Written (signed and dated) informed consent, and capable of co-operating with IMP (and AxMP, as applicable) administration and follow-up.\n- For Module 2: Not a candidate for PARP inhibitor maintenance therapy.\n- For all trial participants: Histologically or cytologically confirmed diagnosis of PDAC with metastatic disease.\n- For all trial participants: Consent for pre- and on-treatment tumour biopsy samples for assessment of molecular markers, including, but not limited to, SMAD4 and gremlin-1. Pre- and on-treatment tumour samples are mandatory in the first instance*. These tumour samples may become optional as considered appropriate by the Sponsor and Investigators based on review of emerging data during the trial. Participants must have disease amenable to biopsy as deemed safe by the Investigator. If there is only 1 measurable lesion, then this should not be used for pre- and on-treatment biopsies and inclusion should be discussed with Sponsor. Archival tumour tissue can be used if adequate tissue for planned analysis is confirmed prior to trial inclusion. Archival tissue sample must be ≤3 months old, with no subsequent treatment and adequate tissue confirmed prior to trial inclusion. Please refer to the Study Laboratory Manual for details on assessment of adequacy of material. *on-treatment tumour samples are not required for participants randomised to Module 2 Expansion Arm B\n- For all trial participants: Measurable disease according to RECIST Version 1.1 (Appendix 2), with at least 1 measurable lesion (not in a previously irradiated area [for Module 1 only: unless radiological progression has occurred]) and not previously biopsied at screening.\n- For all trial participants: ECOG performance status of ≤1 (to be confirmed at screening and within 7 days prior to Cycle 1 Day 1).\n- For all trial participants: Haematological and biochemical indices within the ranges shown in Protocol section 5.1.1, clause 6. These measurements should be performed to confirm the patient’s eligibility to participate in the trial.\n- For all trial participants: Aged 18 years or over at the time consent is given.\n- For Module 2: Investigator determination that the clinical interests of the participant are best served by stopping SoC induction therapy (FOLFIRINOX, or nab-paclitaxel plus gemcitabine) after attainment of a best response of ≥ SD\n- For Module 2: At least ongoing SD or response (CR/PR) after ≥16 weeks of treatment with a SoC first-line induction regimen (FOLFIRINOX, or nab-paclitaxel plus gemcitabine). Ongoing SD or response must be confirmed on the trial baseline scan."}

Exclusion criteria

• {"criterion_text":"- For all trial participants: Prior radiotherapy to the only measurable index lesion unless radiological progression has occurred following completion of radiotherapy.\n- For all trial participants: Any other condition that, in the Investigator’s opinion, would mean that the trial is not in the best interests of the patient.\n- For all trial participants: Ongoing toxic manifestations of previous treatments considered by the Investigator to make the patient unsuitable for the trial.\n- For all trial participants: Previous investigational therapy for the treatment of metastatic PDAC.\n- For all trial participants: Previous concurrent anti-cancer treatment within 28 days or 5 half-lives (whichever is shorter) prior to Cycle 1 Day 1 (e.g., cytoreductive therapy, radiotherapy, immunotherapy, biologic therapy, or cytokine therapy [with the exception of erythropoietin]).\n- For all trial participants: Live vaccinations will not be permitted within 28 days before trial enrolment or randomisation.\n- For all trial participants: Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma.\n- For all trial participants: Prior neo-adjuvant, peri-operative, or adjuvant chemotherapy for non-metastatic pancreatic adenocarcinoma with curative intent unless recurrent (i.e. metastatic) disease is documented more than 6 months since the last dose of systemic therapy. Prior treatment with 5-FU, gemcitabine or capecitabine administered as a radiation sensitiser is allowed, provided that disease progression has occurred more than 6 months since completion of the last dose of chemotherapy or radiotherapy.\n- For all trial participants: Clinically significant/symptomatic third space fluid accumulation (e.g. ascites or pleural effusion).\n- For Module 1: Prior chemotherapy for unresectable disease.\n- For Module 1: Women of childbearing potential. However, those women of childbearing potential who are not already pregnant or breastfeeding, or who agree to discontinue breastfeeding, or who meet the criteria listed in Protocol Section 5.1.4 clause 2 are considered eligible.\n- For all trial participants: Known to be serologically positive for HBV, HCV or HIV. Patients who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have an undetectable HCV RNA by PCR or HBV DNA (by PCR) that is <500 IU/mL before enrolment. Patients who are HBV core antibody positive should receive SoC antiviral therapy during trial treatment.\n- For Module 1: Male patients with partners of childbearing potential or who are pregnant or breastfeeding. However, those patients who meet the criteria listed in Protocol Section 5.1.4 clause 3 are considered eligible.\n- For Module 2: More than one systemic chemotherapy regimen given in the metastatic setting.\n- For all trial participants: Brain or leptomeningeal metastases.\n- For Module 2: Clinically significant ophthalmoscopic findings at the time of screening or history of ophthalmological findings, such as retinal detachment, severe visual impairment, central serous chorioretinopathy, neovascular retinopathy, or retinopathy of prematurity.\n- For Module 2: History of retinal vein occlusion.\n- For Module 2: Any strong inhibitors or inducers of CYP3A (including supplements) within 7 days prior to initiation of Cycle 1 Day 1, and during study treatment for participants in the safety runin and Expansion Arm A.\n- For Module 2: LVEF <40%. This measurement should be performed to confirm the participant’s eligibility to participate in the trial.\n- For Module 2: Participant is unable to swallow cobimetinib intact, without chewing or crushing the tablets (as per the dosing schedule) or is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.\n- For Module 2: Women of childbearing potential. However, those women of childbearing potential who are not already pregnant or breastfeeding, or who agree to discontinue breastfeeding, or who meet the criteria listed in Protocol Section 5.1.5 clause 4 are considered eligible. Participants randomised to Module 2 Expansion Arm B do not need to adhere to the on-trial or post-trial contraception requirements.\n- For Module 2: Male patients with partners of childbearing potential or who are pregnant or breastfeeding. However, those patients who meet the criteria listed in Protocol Section 5.1.5 clause 5 are considered eligible. Participants randomised to Module 2 Expansion Arm B do not need to adhere to the on-trial or post-trial contraception requirements.\n- For all trial participants: Known hypersensitivity to any of the ingredients/excipients in the IMP/s to be administered.\n- For all trial participants: Clinically significant ongoing pulmonary disease, including but not limited to interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis.\n- For all trial participants: History of pulmonary embolism or deep vein thrombosis unless continuing anticoagulant treatment as clinically indicated.\n- For all trial participants: Major thoracic or abdominal surgery from which the patient has not yet recovered.\n- For all trial participants: At high medical risk because of non-malignant systemic disease, including active uncontrolled infection. Patients with previous HCV exposure but no current infection are eligible to participate. Any uncontrolled active systemic infection requiring systemic IV treatment that was completed ≤9 days before Cycle 1 Day 1.\n- For all trial participants: Radiotherapy (for non-metastatic disease) within the last 6 months prior to Cycle 1 Day 1 with the exception of palliative treatment (≤10 Gy single fraction or 25 Gy fractionated total) that has been completed at least 7 days prior to Cycle 1 Day 1.\n- For all trial participants: Significant cardiovascular disease, as outlined in Protocol section 5.1.3 clause 17.\n- For all trial participants: Baseline corrected QTcF >450 ms measured on triplicate ECG (if an average QTcF of >450 ms then the patient is ineligible).\n- For all trial participants: Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase II trial of ginisortamab. Participation in an observational trial or interventional clinical trial that does not involve administration of an IMP and that would not place an unacceptable burden on the patient, in the opinion of the Investigator, would be acceptable.\n- For all trial participants: Current or prior malignancy that could affect safety or efficacy assessment of the IMP or compliance with the protocol or interpretation of results. Patients with curatively treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinomas-in-situ are generally eligible. Patients with asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy, or who require only hormonal therapy and have had normal prostate-specific antigen for >1 year prior to the start of therapy, are eligible for participation in the trial.\n- For all trial participants: Patients with any congenital or acquired immunodeficiency syndrome or who are receiving immunosuppressive therapy (including any dose of systemic corticosteroids), or who are immunosuppressed post-organ transplant. However, patients receiving inhaled corticosteroids and patients with a history of allergy (other than anaphylaxis) are eligible, as are patients with a history of autoimmune disease."}

Primary endpoints

• {"endpoint_text":"- In Module 1, the frequency and causality of AEs, including relatedness, seriousness and severity (graded according to NCI CTCAE Version 5.0), will be assessed by the Investigator.","definition_or_measurement_approach":"Assessed by the Investigator; severity graded according to NCI CTCAE Version 5.0; causality and seriousness documented."}
• {"endpoint_text":"- In Module 1, determining a recommended dose following the review of all available clinically relevant data, including but not limited to toxicity, efficacy and PK data by the Sponsor, CI and PIs.","definition_or_measurement_approach":"Determination based on review of clinically relevant data (toxicity, efficacy, PK) by Sponsor, Chief Investigator and Principal Investigators."}
• {"endpoint_text":"- In Module 1, PFS, defined as the time from date of starting ginisortamab plus SoC nab-paclitaxel and gemcitabine to date of disease progression or date of death, whichever occurs first. DCR, defined as best response of CR or PR or SD (SD of ≥16 weeks) according to RECIST Version 1.1.","definition_or_measurement_approach":"PFS measured as time from start of ginisortamab+SoC to progression or death. DCR = best response of CR or PR or SD (SD ≥16 weeks) according to RECIST v1.1."}
• {"endpoint_text":"- In Module 2, the frequency and causality of AEs, including relatedness, seriousness and severity (graded according to NCI CTCAE Version 5.0), will be assessed by the Investigator.","definition_or_measurement_approach":"Assessed by the Investigator; severity graded per NCI CTCAE v5.0."}
• {"endpoint_text":"- In Module 2, determining a recommended dose following the review of all available clinically relevant data, including but not limited to toxicity, efficacy and PK data by the Sponsor, CI and PIs.","definition_or_measurement_approach":"Determination based on review of toxicity, efficacy and PK data by Sponsor, CI and PIs."}
• {"endpoint_text":"- In Module 2, PFS 1, defined as the time from date of randomisation to date of disease progression or date of death, whichever occurs first.","definition_or_measurement_approach":"PFS1 measured from randomisation to progression or death."}

Secondary endpoints

• {"endpoint_text":"- In Module 1, OS, calculated from date of starting ginisortamab plus SoC nab-paclitaxel and gemcitabine to date of death and ORR, defined as rate of CR plus PR according to RECIST Version 1.1.","definition_or_measurement_approach":"OS = time from start of ginisortamab+SoC to death. ORR = rate of CR+PR per RECIST v1.1."}
• {"endpoint_text":"- In Module 1, DoR, defined as the time from date of the first confirmed CR or PR according to RECIST Version 1.1 to date of disease progression and TTNT, defined as the time from date of starting ginisortamab plus SoC nab-paclitaxel and gemcitabine to date of starting next treatment regimen following discontinuation of trial treatment in this trial.","definition_or_measurement_approach":"DoR = time from first confirmed CR/PR to progression per RECIST v1.1. TTNT = time from start of ginisortamab+SoC to start of next treatment regimen."}
• {"endpoint_text":"- In Module 1, PK parameters for ginisortamab when given with SoC nab-paclitaxel and gemcitabine. For the safety run-in these will include the Cmax, AUC, T1/2, Vss, CL and Ctrough. For the expansion only the Cmax and Ctrough will be monitored.","definition_or_measurement_approach":"PK sampling to derive Cmax, AUC, T1/2, Vss, CL, Ctrough in safety run-in; expansion monitors Cmax and Ctrough."}
• {"endpoint_text":"- In Module 2, PFS 2: defined as the time from date of starting a first-line SoC regimen to date of disease progression or date of death, whichever occurs first.","definition_or_measurement_approach":"PFS2 measured from start of first-line SoC regimen to progression or death."}
• {"endpoint_text":"- In Module 2, OS, calculated from date of starting a first-line SoC regimen to date of death. ORR, defined as rate of best response of CR or PR according to RECIST Version 1.1. DCR, defined as rate of CR, PR, or SD according to RECIST Version 1.1 at 4, 8 and 12 months after randomisation.","definition_or_measurement_approach":"OS from start of first-line SoC to death. ORR per RECIST v1.1. DCR measured at 4, 8 and 12 months after randomisation per RECIST v1.1."}
• {"endpoint_text":"- In Module 2, DoR 1, defined as the time from date of the first confirmed CR or PR according to RECIST Version 1.1 to the date of disease progression. DoR 2: defined as the time from date of randomisation to the date of disease progression, measured in participants who had CR/PR at randomisation. TTNT, defined as the time from date of randomisation to date of starting next treatment regimen.","definition_or_measurement_approach":"DoR1 = time from first confirmed CR/PR to progression. DoR2 = time from randomisation to progression in participants with CR/PR at randomisation. TTNT = time from randomisation to start of next treatment."}
• {"endpoint_text":"- In Module 2, PK parameters for ginisortamab when given with cobimetinib. For the safety run-in these will include the Cmax, AUC, T1/2, Vss, CL, and Ctrough. For the expansion only the Cmax and Ctrough will be monitored.","definition_or_measurement_approach":"PK sampling to derive Cmax, AUC, T1/2, Vss, CL, Ctrough in safety run-in; expansion monitors Cmax and Ctrough."}

Germany

Earliest CTIS Part Ii Submission Date

13-11-2024

Latest Decision Or Authorization Date

20-02-2026

Processing Time Days

464

Number Of Sites

2

Number Of Participants

17

Spain

Earliest CTIS Part Ii Submission Date

19-11-2024

Latest Decision Or Authorization Date

18-02-2026

Processing Time Days

456

Number Of Sites

2

Number Of Participants

17

Norway

Earliest CTIS Part Ii Submission Date

18-11-2024

Latest Decision Or Authorization Date

16-02-2026

Processing Time Days

455

Number Of Sites

1

Number Of Participants

9

Primary sponsor

Full Name

Cancer Research UK

Organisation Type

Patient organisation/association

Country Of Registered Address

United Kingdom