Pan-tumor neoadjuvant basket study of immune check-point inhibition and novel IO combinations (NEOASIS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Netherlands Cancer Institute

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Phenomena and Processes [G] - Immune system processes [G12]

Trial duration

26 Jan 2024 → ongoing

Decision date (initial)

2023-10-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Agenus inc.

External identifiers

EU CT number

2023-505756-21-00

ClinicalTrials.gov

NCT06279130

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Primary objective for pMMR GEA cohort/basket: to determine the efficacy of priming with botensilimab + balstilimab followed by a combination of FLOT chemotherapy with balstilimab/ botensilimab. Efficacy outcome used here is major pathologic response rate, defined as ≤ 10% viable tumor remaining in surgical resection of tumor bed following neoadjuvant therapy.

Primary objective for dMMR rectal cancer OP cohort/basket: to determine the efficacy of botensilimab + balstilimab in dMMR RC. Efficacy outcome used is near-cCR and cCR rate* at the second response evaluation.

Primary objective for dMMR cohorts/baskets: To determine efficacy of botensilimab + balstilimab in dMMR tumors, as determined per basket. Efficacy outcome used here is major pathologic response rate, defined as ≤ 10% viable tumor remaining in surgical resection of tumor bed following neoadjuvant therapy
Primary objective for pMMR cohorts/baskets: to determine efficacy of botensilimab + balstilimab in pMMR tumors, as determined per basket. . Efficacy outcome used here is major pathologic response rate, defined as ≤ 10% viable tumor remaining in surgical resection of tumor bed following neoadjuvant therapy

Primary Objective Safety run-in cohort #1: dMMR tumors (n=10): To determine the safety and feasibility of pre-operative bot + bal in dMMR tumors of any origin.
Primary Objective Safety run-in cohort #2: pMMR tumors (n=10): To determine the safety and feasibility of pre-operative bot + bal in pMMR tumors of any origin.

Secondary objectives 8

1. To assess survival, and the correlation of pathologic response with survival
2. To assess pathologic response rate
3. To assess radiological response rate
4. To assess post-surgical outcome and infectious complications following neoadjuvant immunotherapy
5. Quality of life and functional outcome
6. dMMR rectal cancer organ preservation cohort only: To assess the rate of local excision to achieve organ preservation
7. dMMR rectal cancer organ preservation cohort only: To assess the rate of organ preservation/near-CR
8. dMMR rectal cancer organ preservation cohort only: To assess organ preservation specific survival outcomes

Conditions and MedDRA coding

dMMR tumors consisting of but not limited to; Colorectal cancer, oesophageal cancer, GEJ-cancer, Gastric cancer, Duodenal and small bowel cancer, endometrial cancer, breastcancer, prostate cancer and sarcoma. pMMR tumors constisting of but not limited to; gastric, gastro-esophageal junction (GEJ) and esophageal adenocarcinoma, triple-negative breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Signed written informed consent
2. Patients at least 18 years of age
3. Non-metastatic dMMR and pMMR cancers either fitting within a specific basket or in the “other” cohort (e.g. sarcoma, cervical cancer, head and neck cancers, anal cancer, esophageal SCC)
4. Eligible for study biopsy
5. WHO performance status of 0 or 1
6. Screening laboratory tests must meet the following criteria and should be obtained within 7 days prior to randomization/registration: WBC > 2.0 x 10^9/L, ANC > 1.5x10^9/L, platelets > 100 x 10^9/L, Hemoglobin > 5.0mmol/L. Transfusion is allowed to obtain an adequate hemoglobin level. Liver function tests: total bilirubin < 1.5 upper limit of normal (ULN) (except for subjects with Gilbert syndrome, who can have total bilirubin <3.0 mg/dL); alkaline phosphatase <1.5ULN; transaminases (ASAT/ALAT) <3 x ULN; LDH < 1.5x ULN; Creatinine clearance (Cockcroft-Gault) of >45 ml/min, Albumin > 3.0 g/dL
7. Women of childbearing potential (WOCBP)* must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 20 weeks after the last dose of investigational drug; Non-childbearing potential is defined as: a. Postmenopausal: ≥ 50 years of age and has not had menses for greater than 1 year. b. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and afollicle-stimulating hormone value in the postmenopausal range upon prestudy( screening) evaluation. c. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation.
8. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to registration
9. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving the study treatment and who are sexually active with WOCBP (excluding azoospermic men) will be instructed to adhere to contraception for a period of 28 weeks after the last dose of investigational drug and are not allowed to donate sperm during that timeframe.
10. In case of pMMR tumors: no indication for neoadjuvant therapy according to standard of care, unless adjuvant treatment is considered a standard of care alternative

Exclusion criteria 19

1. Signs of distant metastases on imaging and physical examination
2. No intercurrent illnesses, including but not limited to infections, unstable angina pectoris
3. Underlying medical conditions that, in the investigator’s opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events
4. Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
5. History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
6. Active autoimmune disease or a documented history of autoimmune disease, or other medical conditions requiring systemic steroid or immunosuppressive medications, except for subjects with vitiligo, diabetes mellitus type 1, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis or resolved childhood asthma/atopy not requiring systemic treatment
7. Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
8. Live vaccines in the 4 weeks prior to inclusion
9. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
10. Current pregnancy or breastfeeding
11. Clinical obstruction
12. Clinical symptoms or radiological suspicion of perforation
13. Previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1
14. Prior chemotherapy for any cancer
15. Radiotherapy prior to surgery for disease under study
16. Active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. <10% in 5 years);
17. History of allergy to study drug components
18. History of severe hypersensitivity reaction to any monoclonal antibody
19. Specific for pMMR GEA cohort: Known DPD deficiency; refer local clinical guidance, for DPD status recommendation prior to starting treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Major pathologic response (MPR) rate, defined as <10% residual viable tumor (RVT) in the resection specimen. If after neoadjuvant therapy in situ carcinoma or equivalent non-invasive residual tissue is found upon pathologic assessment, this residual tumor will not be considered in the calculation of RVT. In case of complete resolution of invasive tumor cells and only in situ or equivalent non-invasive tissue (according to tumor type) these tumor will be considered to have a pCR to treatment.
2. Primary endpoint dMMR rectal cancer OP cohort: Primary endpoint is the proportion of patients with either complete or near-complete response at the second clinical response assessment or pathologic evaluation at surgery, whichever comes first

Secondary endpoints 11

1. Pathologic complete response (pCR) defined as no RVT in the primary tumor and locoregional lymph nodes; partial pathologic response (≤50% RVT) and no pathologic response (>50% RVT)
2. Event-free survival defined as time from registration to the date of local, regional or distant disease progression, local, regional or distant recurrence, or death from any cause. Disease progression is defined as a relative increase in sum of diameters of primary tumor of ≥20%, with an absolute increase of ≥5mm. Disease progression during neoadjuvant treatment is considered an event, regardless of whether this leads to a change in treatment. In situ carcinoma and second primary are not events
3. DFS: disease free survival defined as the time from surgery to disease recurrence during follow-up which consists of either local or regional recurrence, metastatic disease or disease-related death. In situ carcinoma and second primary cancers are not considered events.
4. OS: overall survival defined as time from registration until death from any cause.
5. Radiological response according to RECIST 1.1
6. dMMR rectal cancer organ preservation cohort only: Clinical complete and near-complete responses without additional standard of care (SCRT/CRT)
7. dMMR rectal cancer organ preservation cohort only: organ preservation at 1 year: organ preservation is considered to have failed
8. dMMR rectal cander organ preservation cohort only: Proportion of patients undergoing transanal local excision to achieve organ preservation in case of a near complete response
9. dMMR rectal cander organ preservation cohort only: Time to event of organ loss assessed for patients who prefer organ preservation; defined as the length of time from the start date of trial treatment until TME surgery
10. dMMR rectal cancer organ preservation cohort only: Distant metastasis-free survival at 24 and 36 months
11. dMMR rectal cancer organ preservation cohort only: Locoregional regrowth-free survival at 24 and 36 months

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Netherlands Cancer Institute

Sponsor organisation

Netherlands Cancer Institute

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Netherlands Cancer Institute

Contact name

Department of Biometrics

Public contact point

Organisation

Netherlands Cancer Institute

Contact name

Department of Biometrics

Locations

1 EU/EEA country · 1 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 8 files

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

Application history

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