A Phase II trial of ginisortamab in participants with metastatic pancreatic ductal adenocarcinoma

Trial ID: ISRCTN63154609

Other - Phase 2 - Recruiting

Background and study aims In this study the researchers are testing a drug called ginisortamab that blocks a protein called gremlin-1. Gremlin-1 is mainly found outside cancer cells and it stops the function of other proteins called bone morphogenetic proteins (BMPs). BMPs work by suppressing cancer cells as they occur but in cancer this mechanism has often been switched off. Blocking gremlin-1 with ginisortamab is expected to allow BMP function, and we hope this will change the way the cancer cells develop, making them more sensitive to other targeted treatments and/or chemotherapy. The researchers are testing ginisortamab in two different settings (modules), in people with pancreatic ductal adenocarcinoma (PDAC) that has spread (metastatic). Module 1 will involve participants about to start first-line therapy of ginisortamab alongside standard-of-care chemotherapy with nab-paclitaxel and gemcitabine. Module 2 will involve participants whose tumours have either shrunk or not grown significantly with a first-line standard of care regimen (FOLFIRINOX [folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin], or nab-paclitaxel plus gemcitabine) after ≥16 weeks of treatment, who will then be randomised to either i) maintenance therapy of ginisortamab in combination with another treatment called cobimetinib (which can help stop cancer cells from growing and may kill them by blocking two proteins called MEK1 and MEK2) or ii) observation only. The four main aims of this clinical trial are to find out: 1. The best dose of ginisortamab to be given to participants along with nab-paclitaxel and gemcitabine (Module 1) or cobimetinib (Module 2). 2. More about potential side effects of ginisortamab when given with nab-paclitaxel and gemcitabine (Module 1) or cobimetinib (Module 2) and how they can be managed. 3. To see if adding ginisortamab to treatment improves the effectiveness of treatment. 4. What happens to ginisortamab inside the body. Who can participate? Patients aged 18 years and over with metastatic PDAC What does the study involve? Both modules will start with a safety run-in, which aims to find the dose of ginisortamab that is best to give along with other treatments (nab-paclitaxel and gemcitabine [Module 1], or cobimetinib [Module 2]). The dose of ginisortamab could be lowered from the starting dose in this part of the trial, if needed. After each safety run-in is completed, an expansion cohort will open using the best dose of ginisortamab from the safety run-in. We aim to recruit between 6 and 36 participants in each safety run-in and then up to 60 participants in each expansion cohort. Module 2 participants in the expansion cohort will be randomised (randomly allocated) to either i) maintenance therapy of ginisortamab in combination with cobimetinib or ii) observation only, where no medications are given as part of the trial. What are the possible benefits and risks of participating? Ginisortamab is a new drug that has not been tested in very many people. Possible risks and benefits are based on laboratory tests, experience with similar drugs and the limited experience with ginisortamab in people to date. We do not yet have much information about the effects of ginisortamab in humans. Participants in the trial will be monitored closely to find out the effects of ginisortamab. Where is the study run from? Cancer Research UK When is the study starting and how long is it expected to run for? April 2024 to October 2029 Who is funding the study? Cancer Research UK Who is the main contact? 1. Prof. Jeff Evans, Jeff.Evans@beatson.gla.ac.uk 2. Rashida Teladia, Rashida.Teladia@cancer.org.uk 3. Dr. Josephine Salimu, Josephine.Salimu@cancer.org.uk 4. Olivia Frank, Olivia.Frank@cancer.org.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-ginisortamab-for-pancreatic-cancer-that-has-spread

Conditions

• Metastatic pancreatic ductal adenocarcinoma
• Cancer

Interventions

• Ginisortamab

Eligibility

Inclusion criteria

• Current inclusion criteria as of 13/07/2026: Applicable to All Trial Participants: 1. Written (signed and dated) informed consent, and capable of co-operating with IMP/s (and SoC [auxiliary medicinal products], as applicable) administration and follow-up. 2. Histologically or cytologically confirmed diagnosis of PDAC with metastatic disease. 3. 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 a review of emerging data during the trial. Participants must have disease amenable to biopsy as deemed safe by the Investigator. 4. Measurable disease according to RECIST Version 1.1. 5. Eastern Cooperative Oncology Group performance status of ≤1. 6. Haematological and biochemical indices within defined ranges. These measurements should be performed to confirm the patient's eligibility to participate in the trial. 7. Aged 18 years or over at the time consent is given. Module 2 – Additional Inclusion Criteria: 1. 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. 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. 3. Not a candidate for PARP inhibitor maintenance therapy. Previous inclusion criteria as of 07/04/2026: Applicable to All Trial Participants: 1. Written (signed and dated) informed consent, and capable of co-operating with IMP (and SoC) administration and follow-up. 2. Histologically or cytologically confirmed diagnosis of PDAC with metastatic disease. 3. 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 a review of emerging data during the trial. Participants must have disease amenable to biopsy as deemed safe by the Investigator. 4. Measurable disease according to RECIST Version 1.1. 5. Eastern Cooperative Oncology Group performance status of ≤1. 6. Haematological and biochemical indices within defined ranges. These measurements should be performed to confirm the patient's eligibility to participate in the trial. 7. Aged 18 years or over at the time consent is given. Module 2 – Additional Inclusion Criteria: 1. 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. 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. 3. Not a candidate for PARP inhibitor maintenance therapy. Original inclusion criteria: Module 1: 1. Written (signed and dated) informed consent, and capable of co-operating with IMP (and SoC) administration and follow-up. 2. Histologically or cytologically confirmed diagnosis of PDAC with metastatic disease. 3. 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 a review of emerging data during the trial. Participants must have disease amenable to biopsy as deemed safe by the Investigator. 4. Measurable disease according to RECIST Version 1.1. 5. Eastern Cooperative Oncology Group performance status of ≤1. 6. Haematological and biochemical indices within defined ranges. These measurements should be performed to confirm the patient's eligibility to participate in the trial. 7. Aged 18 years or over at the time consent is given.

Exclusion criteria

• Current exclusion criteria as of 13/07/2026: Applicable to All Trial Participants: 1. Prior radiotherapy to the only measurable index lesion unless radiological progression has occurred following completion of radiotherapy. 2. 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. 3. Previous investigational therapy for the treatment of metastatic PDAC. 4. 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, immunotherapy, biologic therapy, or cytokine therapy [with the exception of erythropoietin]). 5. Live vaccinations will not be permitted within 28 days before trial enrolment or randomisation. 6. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma. 7. 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. Exception applies. 8. Clinically significant/symptomatic third space fluid accumulation (e.g. ascites or pleural effusion). 9. Ongoing toxic manifestations of previous treatments considered by the Investigator to make the patient unsuitable for the trial. 10. Brain or leptomeningeal metastases. 11. Clinically significant ongoing pulmonary disease, including but not limited to interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis. 12. History of pulmonary embolism or deep vein thrombosis unless continuing anticoagulant treatment as clinically indicated. 13. Major thoracic or abdominal surgery from which the patient has not yet recovered. 14. At high medical risk because of non-malignant systemic disease, including active uncontrolled infection. Patients with previous hepatitis C virus (HCV) exposure but no current infection are eligible to participate. Any uncontrolled active systemic infection requiring systemic IV treatment that was completed ≤7 days before Cycle 1 Day 1. 15. Known to be serologically positive for hepatitis B virus (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 polymerase chain reaction (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. 16. Known hypersensitivity to any of the ingredients/excipients in the IMP/s to be administered. 17. Significant cardiovascular disease as defined in the trial protocol. 18. Baseline corrected QTcF >450 ms measured on triplicate ECG (if an average QTcF of >450 ms then the patient is ineligible). 19. 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. 20. 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 nonmelanoma 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. 21. 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. Exceptions apply. 22. Any other condition that, in the Investigator’s opinion, would mean that the trial is not in the best interests of the patient. Module 1 – Additional Exclusion Criteria: 1. Prior chemotherapy for unresectable disease 2. Female patients of childbearing potential. However, those patients of childbearing potential who are not already pregnant or breastfeeding, or who agree to discontinue breastfeeding, or who meet the following points are considered eligible: 2.1. Have a negative highly sensitive serum pregnancy test within 7 days before Cycle 1 Day 1 and either: 2.1.1. Agree to one form of highly effective contraception; 2.1.2. Or agree to sexual abstinence. Effective from the date of the negative pregnancy test, throughout the trial and for 6 months after the last administration of IMP or SoC chemotherapy agents (whichever component is administered last. Module 2 – Additional Exclusion Criteria: 1. More than one systemic chemotherapy regimen given in the metastatic setting. 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. 3. History of retinal vein occlusion. 4. 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 run-in and expansion Arm A. 5. LVEF <40%. This measurement should be performed to confirm the participant’s eligibility to participate in the trial. 6. 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 condition that limits the ingestion or gastrointestinal absorption of drugs administered orally. 7. Female patients of childbearing potential. However, those patients of childbearing potential who are not already pregnant or breastfeeding, or who agree to discontinue breastfeeding, or who meet the following points are considered eligible: 7.1. Have a negative highly sensitive serum pregnancy test within 7 days before Cycle 1 Day 1 and either: 7.1.1. Agree to a highly effective contraception method plus a barrier method (condom or other barrier method with spermicide, if available); 7.1.2. Or agree to sexual abstinence. Effective from the date of the negative pregnancy test, throughout the trial and for 4 months after the last administration of IMPs (whichever component is administered last). Participants randomised to Module 2 expansion Arm B do not need to adhere to the on-trial or post-trial contraception requirements. Applicable to Participants in Module 1 and Module 2: 1. Male patients with partners of childbearing potential or who are pregnant or breastfeeding. However, those patients who meet the following points are considered eligible: 1.1. Non-vasectomised males must agree to take measures not to father children by using a barrier method of contraception (condom) or sexual abstinence effective from the date of the first administration of IMP/s and/or SoC chemotherapy agents as applicable, throughout the trial and for 6 months (Module 1) or for 2 weeks (Module 2) after the last administration of IMP/s or SoC chemotherapy agents as applicable (whichever component is administered last). 1.2. Non-vasectomised male patients must also be willing to ensure that any partner who is of childbearing potential uses a highly effective method of contraception or agrees to sexual abstinence 6 months (Module 1) or 4 months (Module 2) after the last administration of IMP/s or SoC chemotherapy agents (whichever component is administered last for both modules). 1.3. Male patients with pregnant or breastfeeding partners must be advised to use barrier method contraception (male condom) to prevent exposure of the foetus or neonate for 6 months (Module 1) or 2 weeks (Module 2) after the last administration of IMP/s and/or SoC chemotherapy agents as applicable (whichever component is administered last for both modules). 1.3.1. All male patients must refrain from donating sperm throughout the trial and for 6 months (Module 1) or 2 weeks (Module 2) after the last administration of IMP/s and/or SoC chemotherapy agents as applicable. Participants randomised to Module 2 expansion Arm B do not need to adhere to the on-trial or post-trial contraception requirements. Previous exclusion criteria as of 07/04/2026: Applicable to All Trial Participants: 1. Previous radiotherapy (except palliative) within 6 months prior, chemotherapy, investigational therapy for metastatic PDAC, other anti-cancer therapy within 28 days or 5 half-lives (whichever is shorter) before the first dose of IMP. 2. Live vaccinations will not be permitted within 28 days before trial enrolment. 3. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma. 4. 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. 5. Clinically significant/symptomatic third space fluid accumulation (e.g. ascites or pleural effusion). 6. Ongoing toxic manifestations of previous treatments considered by the Investigator to make the patient unsuitable for the trial. 7. Brain or leptomeningeal metastases. 8. Clinically significant ongoing pulmonary disease, including but not limited to interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis. 9. History of pulmonary embolism or deep vein thrombosis unless continuing anticoagulant treatment as clinically indicated. 10. Major thoracic or abdominal surgery from which the patient has not yet recovered. 11. 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 ≤7 days before Cycle 1 Day 1. 12. 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 anti-viral therapy during trial treatment. 13. Known hypersensitivity to any of the ingredients/excipients in the IMP to be administered. 14. Significant cardiovascular disease, defined as: 14.1. History of congestive heart failure requiring therapy (New York Heart Association III or IV) or LVEF <40% (moderate or severe); 14.2 History of unstable angina pectoris or myocardial infarction within 6 months prior to trial entry, or current poorly controlled angina (symptoms weekly or more); 14.3 Presence of symptomatic or severe valvular heart disease (severe by local echocardiographic criteria or American Heart Association/American College of Cardiology Stage C or D); 14.4 History of a clinically significant cardiac arrhythmia within 6 months prior to trial entry (asymptomatic atrial fibrillation or asymptomatic first-degree heart block is permitted). 15. Baseline corrected QTcF >450 ms measured on triplicate ECG (if an average QTcF of >450 ms then the patient is ineligible). 16. 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. 17. 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. 18. 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. 19. 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. 20. Any other condition that, in the Investigator’s opinion, would mean that the trial is not in the best interests of the patient. Module 1 – Additional Exclusion Criteria: 1. Prior chemotherapy for unresectable disease Module 2 – Additional Exclusion Criteria: 1. More than one systemic chemotherapy regimen given in the metastatic setting. 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. 3. History of retinal vein occlusion. 4. 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 run-in and expansion Arm A. 5. LVEF <40%. This measurement should be performed to confirm the participant’s eligibility to participate in the trial. 6. 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 condition that limits the ingestion or GI absorption of drugs administered orally. Applicable to Participants in Module 1 and Module 2: 1. Female patients of childbearing potential. However, those patients of childbearing potential who are not already pregnant or breastfeeding, or who agree to discontinue breastfeeding, or who meet the following points are considered eligible: 1.1. Have a negative highly sensitive serum pregnancy test within 7 days before Day 1 and either: 1.1.1. Agree to one form of highly effective contraception; 1.1.2. Or agree to sexual abstinence. 1.2. Effective from the date of the negative pregnancy test, throughout the trial and for 6 months after the last administration of IMP or SoC chemotherapy agents (whichever component is administered last). 1.3. Participants randomised to Module 2 expansion Arm B do not need to adhere to the on-trial or post-trial contraception requirements. 3. Male patients with partners of childbearing potential or who are pregnant or breastfeeding. However, those patients who meet the following points are considered eligible: 3.1. Agree to take measures not to father children by using a barrier method of contraception (condom) or sexual abstinence effective from the date of the first administration of IMP and SoC chemotherapy agents, throughout the trial and for 6 months (Module 1) or for 2 weeks (Module 2) after the last administration of IMPs (whichever component is administered last for both Modules). 3.2. Non-vasectomised male patients must also be willing to ensure that any partner who is of childbearing potential uses a highly effective method of contraception or agrees to sexual abstinence after the last administration of IMPs (whichever component is administered last for both Modules). 3.3. Male patients with pregnant or breastfeeding partners must be advised to use barrier method contraception (male condom) to prevent exposure of the foetus or neonate (for 2 weeks for Module 2) after the last administration of IMPs (whichever component is administered last for both Modules). 3.3.1. All male patients must refrain from donating sperm throughout the trial and for 6 months (Module 1) or 2 weeks (Module 2) after the last administration of IMPs (whichever component is administered last). 3.3.2. Participants randomised to Module 2 expansion Arm B do not need to adhere to the on-trial or post-trial contraception requirements. Previous exclusion criteria: Module 1 exclusion criteria: 1. Previous radiotherapy (except palliative) within 6 months prior, chemotherapy, investigational therapy for metastatic PDAC, other anti-cancer therapy within 28 days or 5 half-lives (whichever is shorter) before the first dose of IMP. 2. Live vaccinations will not be permitted within 28 days before trial enrolment. 3. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma. 4. 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. 5. Clinically significant/symptomatic third space fluid accumulation (e.g. ascites or pleural effusion). 6. Ongoing toxic manifestations of previous treatments considered by the Investigator to make the patient unsuitable for the trial. 7. Brain or leptomeningeal metastases. 8. Clinically significant ongoing pulmonary disease, including but not limited to interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis. 9. History of pulmonary embolism or deep vein thrombosis unless continuing anticoagulant treatment as clinically indicated. 10. Female patients of childbearing potential. However, those patients of childbearing potential who are not already pregnant or breastfeeding, or who agree to discontinue breastfeeding, or who meet the following points are considered eligible: 11. Have a negative highly sensitive serum pregnancy test within 7 days before Day 1 and either: 11.1. Agree to one form of highly effective contraception 11.2. Or agree to sexual abstinence Effective from the date of the negative pregnancy test, throughout the trial and for 6 months after the last administration of IMP or SoC chemotherapy agents (whichever component is administered last). 11.3. Male patients with partners of childbearing potential or who are pregnant or breastfeeding. However, those patients who meet the following points are considered eligible: 11.3.1. Agree to take measures not to father children by using a barrier method of contraception (condom) or sexual abstinence effective from the date of the first administration of IMP and SoC chemotherapy agents, throughout the trial and for 6 months after the last administration of IMP or SoC chemotherapy agents (whichever component is administered last). 11.3.2. Non-vasectomised male patients must also be willing to ensure that any partner who is of childbearing potential uses a highly effective method of contraception or agrees to sexual abstinence for the same duration. 11.3.3. Male patients with pregnant or breastfeeding partners must be advised to use barrier method contraception (male condom) to prevent exposure of the foetus or neonate. 12. Major thoracic or abdominal surgery from which the patient has not yet recovered. 13. At high medical risk because of non-malignant systemic disease, including active uncontrolled infection. 14. Known hypersensitivity to any of the ingredients/excipients in the IMP to be administered.

Sponsor

Cancer Research UK

Source: https://www.isrctn.com/

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