Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers

NCT04491955 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 20013820-C-0138
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Metastatic or refractory/recurrent small bowel and colorectal cancers cannot be cured and are often not helped by standard treatments. Researchers want to find better treatments by testing a combination of drugs. Objective: To learn if a new combination of immunotherapy drugs can shrink tumors in people with advanced small bowel and colorectal cancers. Eligibility: People ages 18 and older who have advanced metastatic or refractory/recurrent small bowel and/or colorectal cancer. Design: Participants will be screened on a separate protocol. They will have a physical exam and medical history. They will have imaging scans. They will have blood and urine tests. Their heart function will be measured. They may have a tumor biopsy. Participants will repeat some of the screening tests during the study. Participants will be put into study groups. Each group will get a combination of the following drugs: CV301 vaccine (modified vaccinia Ankara (MVA)-BN-CV301 and Fowlpox (FPV)-CV301), M7824 (MSB0011359C), and N-803 (Anktiva). Some will also get NHS-IL12 (M9241). Participants will get the CV301 vaccines by injection under the skin. They will get M7824 by intravenous infusion every 2 weeks. They will get N-803 by injection under the skin every 2 or 4 weeks. They may get NHS-IL12 by injection under the skin every 4 weeks. They will take the study drugs for up to 1 year. They will visit the National Institutes of Health (NIH) every 2 weeks. After treatment ends, participants will go to the clinic for a 28-day follow-up visit or have a telephone call. They will be contacted every 3 months for 1 year, and then every 6 months after that for the rest of their life.

Conditions

Small Bowel Cancers; Colorectal Cancers

Keywords

CEA MUC1 Vaccine; CV301; M7824; N-803; NHS-IL12; Bintrafusp alfa; M9241

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate (ORR) for Triple Therapy

  ORR of the combination of (1) Carcinoembryonic antigen (CEA)/Mucin-1 (MUC1) vaccines, (2) N-803 (Anktiva) and (3) M7824 (MSB0011359C) in participants with advanced small bowel and colorectal cancers was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Objective response is a complete or partial radiographic response as defined by RECIST 1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

  one year

• Objective Response Rate (ORR) for Quadruple Therapy

  ORR of the combination of (1) Carcinoembryonic antigen (CEA)/Mucin-1 (MUC1) vaccines, (2) N-803 (Anktiva), (3) M7824 (MSB0011359C) and (4) NHS-IL12 (M9241) in participants with advanced small bowel and colorectal cancers was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Objective response is a complete or partial radiographic response as defined by RECIST 1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

  one year

Secondary Outcomes (6)

• Number of Participants With Grade 3, Grade 4, and/or Grade 5 Adverse Events Related to Triple Therapy

  Date treatment consent signed to date off study, approximately 29 months and 1 day for Cohort 1, Arm 1.

• Number of Participants With Grade 3, Grade 4, and/or Grade 5 Adverse Events Related to Quadruple Therapy

  Date treatment consent signed to date off study, approximately 27 months for Cohort 2, Arm 2a Dose Level 1; 18 months and 29 days for cohort 2, Arm 2a Dose Level 2; and 7 months and 20 days for Cohort 2, Arm 2b, Dose Level 2.

• Progression Free Survival (PFS)

  From time to enrollment up to 35 months

• Overall Survival (OS)

  Up to 35 months

• Duration of Response (DOR)

  Up to 34 months

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 29 months and 1 day for Cohort 1, Arm 1; 27 months for Cohort 2, Arm 2a Dose Level (DL) 1; 18 months and 29 days for cohort 2, Arm 2a DL 2; and 7 months and 20 days for Cohort 2, Arm 2b, DL 2.

Study Arms (3)

1/Arm 1

EXPERIMENTAL

CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).

Biological: CV301; Drug: MSB0011359C; Drug: N-803

2/Arm 2A

EXPERIMENTAL

CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12.

Biological: CV301; Drug: MSB0011359C; Drug: N-803; Drug: NHS-IL12

3/Arm 2B

EXPERIMENTAL

CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.

Biological: CV301; Drug: MSB0011359C; Drug: N-803; Drug: NHS-IL12

Interventions

CV301 BIOLOGICAL

CV301 vaccine consists of MVA-BN-CV301 and FPV-CV301. MVA-BN-CV301 (4 x 10\^8 infectious units/0.5 mL each) will be administered as four subcutaneous injections on D1 and D15. Starting on D29, FPV-CV301 (1 x 10\^9 infectious units/ 0.5mL) will be administered as a single subcutaneous injection every 4 weeks on Arm 1 or every 6 weeks on Arm 2A and 2B for up to one year.

1/Arm 1; 2/Arm 2A; 3/Arm 2B

MSB0011359C DRUG

Subjects will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200 mg or 300 mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.

1/Arm 1; 2/Arm 2A; 3/Arm 2B

N-803 DRUG

N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every four weeks on Arm 1. N-803 will be administered at as dose of 10 (Micro)g/kg by SC injection every 4 weeks on Arm 2A and Arm 2B.

1/Arm 1; 2/Arm 2A; 3/Arm 2B

NHS-IL12 DRUG

NHS-IL12 will be given via subcutaneous injection at a dose of 8 mcg/kg every 4 weeks or 16 mcg/kg for the first 4 injections and 8 mcg/kg thereafter on Arms 2A and 2B.

2/Arm 2A; 3/Arm 2B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with cytologically or histologically confirmed locally advanced or metastatic small bowel or colorectal adenocarcinoma
• Subjects must have received two prior lines of systemic therapy unless the subject is not eligible to receive standard therapy or declines standard treatment
• Subjects must have measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status \<= 2
• Adequate hematologic function at screening, as follows:
• Absolute neutrophil count (ANC) \>=1 x 10\^9/L
• Hemoglobin \>= 9 g/dL
• Platelets \>= 75,000/microliter
• Adequate renal and hepatic function at screening, as follows:
• \- Serum creatinine \<= 1.5 x upper limit of normal (ULN) OR
• Measured or calculated creatinine clearance \>= 40 mL/min for participant with creatinine levels \> 1.5 X institutional ULN (glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl);
• Bilirubin \<= 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin \<= 3.0 x ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<= 2.5 x ULN, unless liver metastases are present, then values must be \<= 3 x ULN)
• The effects of the immunotherapies on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment and up to two months after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Participants serologically positive for human immunodeficiency virus (HIV), Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative polymerase chain reaction (PCR). HIV positive participants must have cluster of differentiation 4 (CD4) count \>= 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy for at least 4 weeks and have no reported opportunistic infections or Castleman s disease within 12 months prior to enrollment.

You may not qualify if:

• Participants with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the participant is otherwise suitable for enrollment. Additionally, current therapies (e.g., maintenance capecitabine) may be continued where in the opinion of the investigator stopping such therapies may increase the risk of disease progression. Also, participants may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast).
• Participants with microsatellite unstable or mismatch repair deficient disease.
• Major surgery within 28 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).
• Known life-threatening side effects resulting from prior checkpoint inhibitor therapy (e.g., colitis, pneumonitis, fulminant hepatitis which led to permanent discontinuation of prior checkpoint therapy). Autoimmune toxicity which was not life threatening (e.g., arthritis) or did not lead to discontinuation of prior checkpoint therapy is allowed.
• Known active brain or central nervous system metastasis (less than a month out from definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (\<3 months) or clinically significant cerebrovascular accident (\<3 months). In order to be eligible participants must have repeat central nervous system (CNS) imaging at least a month after definitive treatment showing stable CNS disease. Participants with evidence of intra-tumoral or peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is grade \<= 1 and has been shown to be stable on two consecutive imaging scans.
• Pregnant women are excluded from this study because these drugs have not been tested in pregnant women and there is potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these immunotherapies, breastfeeding should be discontinued if the mother is treated on this protocol.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with exception of:
• Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or other mild autoimmune disorders not requiring immunosuppressive treatment;
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses \<= 10 mg of prednisone or equivalent per day;
• Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable;
• Subjects on systemic intravenous or oral corticosteroid therapy with the exception of physiologic doses of corticosteroids (\<= the equivalent of prednisone 10 mg/day) or other immunosuppressive agents such as azathioprine or cyclosporin A are excluded on the basis of potential immune suppression. For these subjects these excluded treatments must be discontinued at least 1 weeks prior to enrollment for recent short course use (\<= 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (\> 14 days). In addition, the use of corticosteroids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study.
• Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events or other illness considered by the Investigator as high risk for investigational drug treatment.
• Subjects unwilling to accept blood products as medically indicated.
• History of second malignancy within 3 years of enrollment except for the following: adequately treated localized skin cancer, cervical carcinoma in situ, superficial bladder cancer, or other localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk chronic lymphocytic leukemia (CLL).
• Subjects with a known severe hypersensitivity reaction to a monoclonal antibody (grade \>= 3 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE v5) will be evaluated by the allergy/immunology team prior to enrollment.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Bracken-Clarke D, Pastor DM, Marte JL, Donahue RN, Hodge JW, Cordes L, Floudas CS, Tschernia NP, Karzai F, Brownell I, Turkbey EB, Soon-Shiong P, Schlom J, Gulley JL, Maeng HM, Strauss J, Redman JM. The Quadruple Immunotherapy for Colorectal Cancer (QuICC) Trial for Mismatch Repair-Proficient Metastatic Colorectal Cancer. Oncologist. 2026 Jan 10:oyag008. doi: 10.1093/oncolo/oyag008. Online ahead of print.

  PMID: 41520164 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

ALT-803; NHS-IL12 immunocytokine

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Results Point of Contact

• Title: Dr. Hoyoung Maeng
• Organization: National Cancer Institute

hoyoung.maeng@nih.gov

240-781-3253

Study Officials

• Hoyoung Maeng, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 29, 2020
• First Posted: July 30, 2020
• Study Start: September 22, 2020
• Primary Completion: October 25, 2022
• Study Completion: August 16, 2024
• Last Updated: April 24, 2025
• Results First Posted: November 14, 2023

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the Database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)