Pan-tumor Neoadjuvant Basket Study of Immune Check-point Inhibition and Novel Immuno-oncology Combinations (NEOASIS)

In this study, the efficacy of botensilimab and balstilimab in mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) tumors will be assessed.

Study Overview

• Status: Recruiting
• Conditions: Resectable MMR-deficient Solid Tumors; Resectable MMR-proficient Solid Tumors
• Intervention / Treatment: Drug: botensilimab; Drug: balstilimab

Detailed Description

The NEOASIS study is an adaptive, pan-cancer, single-center, open-label, basket study assessing the efficacy of botensilimab and balstilimab in patients with resectable dMMR and pMMR solid tumors of various origins. Patients will be included in baskets according to tumor type and mismatch repair (MMR) status and will receive 2 cycles of immunotherapy followed by surgery.

The trial will commence with two safety run-in cohorts: one for patients with dMMR tumors and one for patients with pMMR tumors that will run in parallel. These safety run-in cohort will be used to assess safety and feasibility of pre-operative botensilimab + balstilimab. Data from the safety run-in cohorts will be used to determine the dosing and scheduling to be used in the MMR-specific cohorts of the main study. Safety will be assessed according to dose limiting toxicities. In the run-in cohorts, the first five patients will receive botensilimab 25mg intravenously (IV) on Day1 plus balstilimab 450mg IV on Day1 and Day22. Patients 6-10 will receive botensilimab 50mg IV on Day1 plus balstilimab 450mg IV on Day1 and Day22 followed by surgery 8 weeks after registration.

After full accrual of the run-in cohorts, MMR-specific baskets including a "other cancers" basket will start accrual with the optimal dose and schedule as determined in the safety run-in followed by surgery 8 weeks after registration. The MMR-specific baskets are designed with a Simon's 2 stage design in which first 8 patients will be included, if in the first 8 patients >2 Major pathological responses are reported (defined as ≤10% residual viable tumor) accrual of 10 more patients will continue for a total of 18 patients per basket.

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Marieke van de Belt, MsC; Phone Number: 0205129111; Email: m.vd.belt@nki.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1066 CX
      • Recruiting
      • The Netherlands Cancer Institute
      • Contact: Marieke van de Belt, MsC
      • Principal Investigator: Myriam Chalabi, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed written informed consent
2. Patients at least 18 years of age
3. Non-metastatic, newly diagnosed dMMR and pMMR cancers either fitting within a specific basket or in the "other" cohort (e.g. sarcoma, head and neck cancers, anal cancer, esophageal SCC)
4. 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;
5. Eligible for study biopsy
6. World health organization (WHO) performance status of 0 or 1
7. Screening laboratory tests must meet the following criteria and should be obtained within 7 days prior to randomization/registration: White blood cell count (WBC > 2.0 x 10^9/L, Absolute neutrophil count (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 <1.5 ULN; transaminases (ASAT/ALAT) <3 x ULN; Lactate dehydrogenase (LDH) < 1.5x ULN; Creatinine clearance (Cockcroft-Gault) of >45 ml/min, Albumin > 3.0 g/dL

8. 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:

   1. Postmenopausal: ≥ 50 years of age and has not had menses for greater than 1 year.
   2. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and a follicle- stimulating hormone value in the postmenopausal range upon pre-study(screening) evaluation.
   3. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation.
9. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of cycle 1 day 1
10. 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.

Exclusion Criteria:

1. Signs of distant metastases on imaging and physical examination
2. Clinical obstruction
3. Clinical symptoms or radiological suspicion of perforation
4. Previous treatment with immune checkpoint inhibitors including but not limited to anti-CTLA4 or anti-PD1
5. Prior chemotherapy for any cancer
6. Radiotherapy prior to or planned post-surgery radiotherapy for disease under study
7. 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)

8. Allergies and Adverse Drug Reaction:

   1. History of allergy to study drug components
   2. History of severe hypersensitivity reaction to any monoclonal antibody
9. Intercurrent illnesses, including but not limited to infections, unstable angina pectoris
10. 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
11. Positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
12. History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
13. 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
14. 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
15. Live vaccines in the 4 weeks prior to inclusion
16. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
17. Current pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: pMMR Safety run-in 1; 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 25mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)
Experimental: pMMR Safety run-in 2; 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 50mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)
Experimental: dMMR Safety run-in 1; 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 25mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)
Experimental: dMMR Safety run-in 2; 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 50mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)
Experimental: dMMR Colorectal basket; Patients with resectable colon and rectal cancer will be treated with the regimen assesses as safe and feasible in the dMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If >2 major pathological responses are observed accrual will continue to a total of 18 patients.	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)
Experimental: dMMR Gynaecological oncology basket; Patients with resectable endometrial, cervical and ovarian cancer will be treated with the regimen assessed as safe and feasible in the dMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If >2 major pathological responses are observed accrual will continue to a total of 18 patients.	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)
Experimental: dMMR Upper gastro-intestinal cancer basket; Patients with resectable oesophageal (adenocarcinoma), gastro-oesophageal junction, gastric and small bowel cancer will be treated with the regimen assessed as safe and feasible in the dMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If >2 major pathological responses are observed accrual will continue to a total of 18 patients.	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)
Experimental: dMMR "other cancers" baskets; Patients with resectable solid tumors of various origins such as but not limited to breast-, prostate-, bladder cancer, Head&Neck SCC, oesophageal SCC and sarcoma will be treated with the regimen assessed as safe and feasible in the dMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If >2 major pathological responses are observed accrual will continue to a total of 18 patients.	Drug: botensilimab; Anti cytotoxic T-lymphocyte associated protein-4 (anti-CTLA4); Drug: balstilimab; Anti programmed cell death protein-1 (anti-PD1)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major pathological response rate	Percentage of patients in which a major pathologic response (MPR) is reported, defined as <10% residual viable tumor (RVT) in the resection specimen.	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological response rates	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)	Week 8
Event free survival	Event-free survival defined as time from registration to the date of disease progression, local, regional or distant recurrence, occurrence of a second primary cancer or death from any cause.	3 years
Disease free survival	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.	3 years
Overall survival	Overall survival defined as time from registration until death from any cause.	5 years
Radiological response	Radiological response measured according to RECIST 1.1	Week 8

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Agenus Inc.
• Investigators: Principal Investigator: Myriam Chalabi, MD PhD, The Netherlands Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2024
• Primary Completion (Estimated): January 29, 2029
• Study Completion (Estimated): January 29, 2034

Study Registration Dates

• First Submitted: February 13, 2024
• First Submitted That Met QC Criteria: February 22, 2024
• First Posted (Estimated): February 26, 2024

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: N23NEO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No