A multicentric phase II trial evaluating volrusotmig in patients with mature tertiary lymphoid structures solid tumors.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Bergonie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2023-10-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-503451-94-00

ClinicalTrials.gov

NCT05888857

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Pharmacodynamic, Pharmacogenomic, Efficacy

PRIMARY OBJECTIVE
• To evaluate the antitumour activity of volrustomig (MEDI5752) independently for two cohorts of patients:
o Cohort A: patients with TLS+ IO-naïve solid tumour (miscellaneous)
o Cohort B: patients with TLS+ PD1/PDL1-experienced solid tumour (miscellaneous)
• Antitumor activity will be assessed in terms of objective response rate (ORR) based on RECIST v1.1.

Secondary objectives 4

1. Independently for each cohort, to evaluate the antitumour activity of volrustomig (MEDI5752) in terms of additional efficacy measures : 24-weeks clinical benefit rate as per RECIST v1.1, best overall response as per RECIST v1.1, duration of response as per RECIST v1.1, Progression-free survival as per RECIST v1.1, growth modulation index.
2. Independently for each cohort, to evaluate the antitumour activity of volrustomig in terms of overall survival.
3. Independently for each cohort, to evaluate the safety (adverse event data) of volrustomig
4. Independently for each cohort, to assess the prognostic role and pharmacodynamics of exploratory biomarkers in tissue and blood, and their association with disease status, mechanisms of resistance, and/or response to study treatment.

Conditions and MedDRA coding

Adult participants with metastatic (advanced) solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Histologically confirmed solid tumor
2. IO-naïve patients (cohort A) OR patients with secondary resistance to PD1/PDL1 inhibitors (cohort B)
3. Patients in cohort B: a) have to be previously treated with PD-L1/PD-1 inhibitors (investigational or approved), b) must have experienced initial clinical benefit (stable disease or better) from checkpoint inhibitor therapy for at least 4 months in which there was at least one interval scan prior to 4 months demonstrating no progression of disease
4. Presence of mature tertiary lymphoid structures (TLS) by IHC as described in protocol section 3.2.4. Except if presence of TLS has been already confirmed by Biopathological platform at Bergonié Institute, presence of TLS should be confirmed by central review based on FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample (archived or newly obtained by biopsy for research purpose). Note that the presence of TLS should be determined by central analysis if not available before
5. Advanced unresectable or metastatic solid disease
6. Measurable disease according to RECIST v1.1 outside any previously irradiated field (except if progressive as per RECIST v1.1 at inclusion). At least one site of disease must be uni-dimensionally ≥ 10 mm
7. At least one tumor site that can be biopsied for research purpose
8. Age ≥ 18 years
9. Body weight > 35 kg
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
11. Life expectancy > 3 months
12. Adequate hematological, renal, metabolic, hepatic and cardiac functions: a) Hemoglobin ≥ 9 g/dl (in the absence of transfusions within 14 days prior to enrolment); absolute neutrophil count (ANC) ≥ 1.5 G/l (in the absence of growth factor support within 14 days prior to enrolment), platelet count ≥ 100 G/l, b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normality (ULN) (≤ 5 x ULN in case of liver metastasis for AST and ALT) c) Total bilirubin ≤ 1.5 x ULN in the absence Gilbert’s syndrome ; ≤ 3 x ULN if the subject has Gilbert’s syndrome. d) Serum albumin ≥ 25g/l. e) Calculated creatinine clearance (CrCl) ≥ 45 ml/min (by modified Cockcroft-Gault (Rostocker et al 2007). f) Troponine I or T ≤ ULN (per institutional guidelines and/or not clinically significant per investigator judgement), g) Baseline QTcF ≤ 480 msec, h) LVEF ≥ 50% as assessed by echocardiography or MUGA
13. Disease progression on prior treatment, or first line setting for non small cell lung cancer, mesothelioma, pancreatic cancer, gastric cancer, biliary tract cancer, bladder cancer, soft-tissue sarcoma, triple-negative breast cancer, unknown primary carcinoma, MSS colorectal cancer, ovarian cancer, endometrial cancer, and cervical cancer. Note that no more than three lines of systemic treatment for metastatic disease are allowed and that patients with EGFR-mutated, BRAF-mutated, ALK rearranged or RET-rearranged non-small cell lung cancer must have progressed on prior approved regimens
14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 5.0)), Note : for subjects who have received prior anti-PD1, anti PD-L1 or anti-CTLA-4 : subjects with an endocrine AE of ≤ Grade 2 are permitted to enroll if they are stably maintained on appropriate endocrine replacement therapy and are asymptomatic
15. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry. Pregnancy test should be repeated within 24 hours prior to receiving the first dose of study medication
16. Women must agree to use at least one medically highly effective method of contraception from screening, throughout the treatment period and for 90 days after discontinuation of treatment. Men must agree to use a medically acceptable method of contraception from screening, throughout the treatment period and for 90 days after discontinuation of treatment. Highly effective methods for contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year
17. Voluntary signed and dated written informed consents prior to any specific study procedure
18. Patients with a social security in compliance with the French law

Exclusion criteria 30

1. Any anticancer treatment within 21 days or 5 half-lives (whichever is shorter) prior to start of study treatment
2. Whole brain radiotherapy within 14 days prior to start of study treatment
3. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
4. Stereotactic radiosurgery within 7 days prior to start of study treatment
5. Major surgery within 4 weeks prior to start of study treatment or still recovering from prior surgery (note: local surgery of isolated lesions for palliative intent is acceptable)
6. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding
7. History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study or confounds the ability to interpret data from the study
8. Prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated non melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated in situ carcinoma without evidence of disease, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma
9. Any prior Grade ≥ 3 imAE while receiving immunotherapy or any unresolved imAE > Grade 1
10. For subjects who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 : Subject must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy, must not have experienced a ≥ grade 3 imAE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy, must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, must not have experienced recurrence of an AE if rechallenged, and must not currently require maintenance doses of > 10 mg prednisone or equivalent per day
11. Symptomatic or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated or untreated CNS metastases are eligible, provided that all of the following criteria are met : a) No ongoing requirement for corticosteroids as therapy for CNS metastases b) No evidence of interim progression between completion of CNS-directed therapy and screening radiographic study c) No history of intracranial hemorrhage or spinal cord hemorrhage
12. History of leptomeningeal disease or cord compression
13. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN)
14. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX®) are allowed
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiomyopathy of any etiology, symptomatic congestive heart failure (as defined by New York Heart Association class > 2), uncontrolled hypertension, unstable angina pectoris, history of myocardial infarction within the past 12 months, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions associated with diarrhea
16. Cerebrovascular accident within 6 months prior to enrolment
17. Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable
18. Active or history of autoimmune disease, immune deficiency or inflammatory disorders, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, sarcoidosis syndrome, rheumatoid arthritis, hypophysitis, uveitis inflammatory bowel disease, diverticulits (with the exception of diverticulosis), antiphospholipid antibody syndrome, Wegener granulomatosis, Graves’ disease, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: a) Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study, b) Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study, c) Patients with celiac disease controlled by diet alone, d) Patients with eczema, psoriasis, lichen simplex chronicus, alopecia or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met : - Rash must cover < 10% of body surface area, - Disease is well controlled at baseline and requires only low-potency topical corticosteroids, - No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
19. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of asymptomatic radiation pneumonitis in the radiation field (fibrosis) is permitted
20. Evidence of the following infections: a) Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), b) or human immunodeficiency virus (HIV) (positive for HIV-1 or HIV-2 antibodies), c) or active or uncontrolled hepatitis B (HBV) or hepatitis C (HCV). Participants are eligible if they: - Have controlled hepatitis C viral load defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy - Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis - Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii below: - Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: i. HBV DNA viral load <100 IU/mL ii. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT <3 × ULN, which are not attributable to HBV infection iii. Start or maintain antiviral treatment if clinically indicated as per the investigator d) or active hepatitis A
21. Any contraindication to biopsy for the research
22. Participation in a study involving a medical or therapeutic intervention in the last 30 days
23. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons
24. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
25. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
26. Prior allogeneic stem cell or solid organ transplantation
27. Treatment with a live, attenuated vaccine within 30 days prior to initiation of study treatment, or anticipation of need for such a vaccine during MEDI5752 treatment or within 30 days after the final dose of MEDI5752
28. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α-agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: a) Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor approval has been obtained, b) Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study, c) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection)
29. History of severe allergic anaphylactic reaction to chimeric or humanized antibodies or fusion proteins
30. Known hypersensitivity to Chinese hamster ovary cell products, to any component of the MEDI5752 formulation or to any human globulin therapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Antitumour activity will be assessed in terms of objective response rate (ORR) RECIST v1.1, independently for each cohort :

Secondary endpoints 8

1. 24-weeks clinical benefit rate (CBR)
2. Best overall response throughout the treatment period (BoR)
3. Duration of response from documentation of tumour response to disease progression (DoR)
4. 1-year and 2-year progression-free survival (PFS)
5. Growth modulation index (GMI)
6. 1-year and 2-year overall survival (OS)
7. Safety profile of volrustomig
8. Correlate tumor microenvironment features (including but not limited to density of immune cells, expression of exhaustion markers), plasma metabolomics, plasma proteomics with patient outcome (objective response rate, PFS and OS).

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Institut Bergonie

Contact name

Pr Antoine ITALIANO

Public contact point

Organisation

Institut Bergonie

Contact name

Mme Aurore Barthod-Malat

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Results and documents

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

Documents 7 files

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

Application history

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