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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cancer Research UK

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Digestive System Diseases [C06]

Trial duration

15 Jan 2025 → ongoing

Decision date (initial)

2024-12-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Cancer Research UK

External identifiers

EU CT number

2024-514129-43-00

ISRCTN

ISRCTN63154609

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Therapy, Others

The primary objectives for Module 1 of the study are:
1. To assess the safety and toxicity profile of ginisortamab when given with SoC nab-paclitaxel and gemcitabine first-line therapy.
2. To identify a recommended dose of ginisortamab when given with SoC nab-paclitaxel and gemcitabine first-line therapy.
3. To document anti-tumour activity of ginisortamab when given with SoC nab-paclitaxel and gemcitabine first-line therapy.

The primary objectives for Module 2 of the study are:
1. To assess the safety and toxicity profile of ginisortamab when given in combination with cobimetinib as maintenance therapy.
2. To identify a recommended dose of ginisortamab when given in combination with cobimetinib as maintenance therapy.
3. To document possible anti-tumour activity of ginisortamab when given in combination with cobimetinib as maintenance therapy in participants with ongoing response or disease stabilisation after ≥16 weeks of a SoC regimen.

Secondary objectives 4

1. In Module 1, to further describe anti-tumour activity of ginisortamab when given with SoC nab-paclitaxel and gemcitabine first-line therapy.
2. In Module 1, to investigate PK parameters of ginisortamab in participants when given with SoC nab-paclitaxel and gemcitabine first-line therapy.
3. In Module 2, to further describe anti-tumour activity of ginisortamab when given in combination with cobimetinib as maintenance therapy in participants with ongoing response or disease stabilisation after ≥16 weeks of a SoC regimen.
4. In Module 2, to investigate PK parameters of ginisortamab in participants when given in combination with cobimetinib as maintenance therapy (Arm A).

Conditions and MedDRA coding

Metastatic pancreatic ductal adenocarcinoma

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration, Federal Agency For Medicines And Health Products

Plan to share IPD

Yes

IPD plan description

The datasets generated during and/or analysed during the current study will be available upon request. Data from this trial and the final clinical study protocol will be submitted to a public registry and will be available immediately following publication, with no end date. Individual deidentified participant data that underly the results reported will be shared with researchers whose proposed use of the data is approved by a review committee of the Sponsor. All requests made within 5 years from end of trial will be considered; requests made subsequently will be considered where possible. Requests should be submitted to [email protected].

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 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.
2. For all trial participants: Histologically or cytologically confirmed diagnosis of PDAC with metastatic disease.
3. 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
4. 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.
5. For all trial participants: ECOG performance status of ≤1 (to be confirmed at screening and within 7 days prior to Cycle 1 Day 1).
6. 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.
7. For all trial participants: Aged 18 years or over at the time consent is given.
8. 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
9. 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.
10. For Module 2: Not a candidate for PARP inhibitor maintenance therapy.

Exclusion criteria 33

1. For all trial participants: Prior radiotherapy to the only measurable index lesion unless radiological progression has occurred following completion of radiotherapy.
2. 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.
3. For all trial participants: Known hypersensitivity to any of the ingredients/excipients in the IMP/s to be administered.
4. 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.
5. For all trial participants: Significant cardiovascular disease, as outlined in Protocol section 5.1.3 clause 17.
6. 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).
7. 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.
8. 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.
9. 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.
10. 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.
11. For all trial participants: Ongoing toxic manifestations of previous treatments considered by the Investigator to make the patient unsuitable for the trial.
12. For all trial participants: Previous investigational therapy for the treatment of metastatic PDAC.
13. 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]).
14. For all trial participants: Live vaccinations will not be permitted within 28 days before trial enrolment or randomisation.
15. For all trial participants: Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma.
16. 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.
17. For all trial participants: Clinically significant/symptomatic third space fluid accumulation (e.g. ascites or pleural effusion).
18. For Module 1: Prior chemotherapy for unresectable disease.
19. 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.
20. 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.
21. For Module 2: More than one systemic chemotherapy regimen given in the metastatic setting.
22. For all trial participants: Brain or leptomeningeal metastases.
23. 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.
24. For Module 2: History of retinal vein occlusion.
25. 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.
26. For Module 2: LVEF <40%. This measurement should be performed to confirm the participant’s eligibility to participate in the trial.
27. 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.
28. 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.
29. 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.
30. For all trial participants: Clinically significant ongoing pulmonary disease, including but not limited to interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis.
31. For all trial participants: History of pulmonary embolism or deep vein thrombosis unless continuing anticoagulant treatment as clinically indicated.
32. For all trial participants: Major thoracic or abdominal surgery from which the patient has not yet recovered.
33. 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 ≤7 days before Cycle 1 Day 1.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.

Secondary endpoints 7

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cancer Research UK

Sponsor organisation

Cancer Research UK

Address

2 Redman Place

City

London

Postcode

E20 1JQ

Country

United Kingdom

Scientific contact point

Organisation

Cancer Research UK

Contact name

Professor Jeff Evans

Public contact point

Organisation

Cancer Research UK

Contact name

Cancer Research UK Center for Drug Development

Locations

3 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 40 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications