Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers
Condition: Small Bowel Cancers; Colorectal Cancers
MeSH terms: Colorectal Neoplasms
Intervention: CV301; MSB0011359C; N-803; NHS-IL12
Intervention description: 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.; 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.; 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.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CEA MUC1 Vaccine; CV301; M7824; N-803; NHS-IL12; Bintrafusp alfa; M9241

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.
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Subjects with cytologically or histologically confirmed locally advanced or metastatic
             small bowel or colorectal adenocarcinoma

          2. Subjects must have received two prior lines of systemic therapy unless the subject is
             not eligible to receive standard therapy or declines standard treatment

          3. Subjects must have measurable disease

          4. Eastern Cooperative Oncology Group (ECOG) performance status <= 2

          5. Adequate hematologic function at screening, as follows:

               -  Absolute neutrophil count (ANC) >=1 x 10^9/L

               -  Hemoglobin >= 9 g/dL

               -  Platelets >= 75,000/microliter

          6. 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)

          7. 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.

          8. 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.

          9. Ability of subject to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA:

          1. 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).

          2. Participants with microsatellite unstable or mismatch repair deficient disease.

          3. Major surgery within 28 days prior to the first drug administration (minimally
             invasive procedures such as diagnostic biopsies are permitted).

          4. 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.

          5. 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.

          6. 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.

          7. 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.

          8. 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.

          9. Subjects unwilling to accept blood products as medically indicated.

         10. 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).

         11. 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.

         12. Receipt of any organ transplantation requiring ongoing immunosuppression.

         13. Receipt of prior lymphodepleting chemotherapy (e.g., cyclophosphamide or fludarabine
             at standard lymphodepleting doses).