Clinical Trials /

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

NCT04491955

Description:

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 (MVA-BN-CV301 and FPV-CV301), M7824, and N-803. Some will also get NHS-IL12. 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 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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers
  • Official Title: Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers

Clinical Trial IDs

  • ORG STUDY ID: 200138
  • SECONDARY ID: 20-C-0138
  • NCT ID: NCT04491955

Conditions

  • Small Bowel Cancers
  • Colorectal Cancers

Interventions

DrugSynonymsArms
CV3011/Arm 1
MSB0011359C1/Arm 1
N-8031/Arm 1
NHS-IL122/Arm 2A

Purpose

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 (MVA-BN-CV301 and FPV-CV301), M7824, and N-803. Some will also get NHS-IL12. 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 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.

Detailed Description

      Background:

        -  Metastatic or refractory/recurrent small bowel and colorectal cancers are incurable and
           poorly palliated by standard therapies. There is an unmet need for active treatments for
           these tumors.

        -  To date immunotherapies including anti PD-1 or anti PD-L1 inhibitors have proven largely
           ineffective for the vast majority of these cancers.

             -  In microsatellite stable (MSS) colorectal cancer (>95% of these cancers) the
                response rate to checkpoint inhibitors has been <5%.

             -  Preclinical studies suggest that the use of different combinations of multiple
                immunotherapy agents may improve anti-tumor efficacy. These studies have employed
                (1) a vaccine targeting a tumor associated antigen, (2) an IL-15 superagonist
                (N-803, also known as ALT-803), (3) an anti-PD-L1 MAb or a bifunctional fusion
                protein targeting PD-L1 and TGF beta (M7824), and (4) a tumor targeted
                immunocytokine (NHS-IL12).

      Objectives:

      To evaluate the objective response rate (ORR) according to Response Evaluation Criteria
      (RECIST 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting CEA and
      MUC1, (2) N-803 and (3) M7824; and of the combination of (1) CV301, (2) N-803, (3) M7824 and
      (4) NHS-IL12 (M9241) in subjects with advanced checkpoint naive MSS small bowel and
      colorectal cancers.

      Eligibility:

        -  Age >= 18 years old

        -  Subjects with cytologically or histologically confirmed locally advanced or metastatic
           small bowel or colorectal adenocarcinomas.

        -  Prior first line systemic therapy is required unless the patient declines standard
           treatment after appropriate counseling has been provided.

        -  Subjects must have measurable disease.

      Design:

        -  This is a phase II trial of combination immunotherapy, with a brief dose escalation
           portion for Arm 2.

        -  The trial will be conducted using a Simon optimal two-stage design in each Phase II Arm.

        -  Patients will be enrolled on the following arms in sequential order: (1) Arm 1: CV301 +
           M7824 + N-803, (2) Arm 2A and Arm 2B: CV301 + M7824 + N-803 + NHS-IL12; NHS-IL12 dose
           level will be evaluated in Arm 2A prior to further enrollment in Arm 2B.

        -  The first six patient on arm 1 will be evaluable for dose limiting toxicities (DLTs) and
           accrual will only continue to 9 patients on that arm if less than 2 out of the first 6
           patients experience a DLT.

        -  In Arm 2B, patients will receive 4 drug treatments (CV301 + M7824 + N-803 + NHSIL12),
           but the dose level of NHS-IL12 will first be determined during a 3-level dose escalation
           portion, Arm 2A. Following determination of the MTD or highest safe dose evaluated, the
           6 patients at that dose level will be included among the initial 9 patients for the
           first stage of that arm.

        -  If two or more out of nine patients have objective responses on a given arm that arm
           will be expanded to enroll 20 evaluable patients.
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm 1ExperimentalCEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).
  • CV301
  • MSB0011359C
  • N-803
2/Arm 2AExperimentalCEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHSIL12.
  • CV301
  • MSB0011359C
  • N-803
  • NHS-IL12
3/Arm 2BExperimentalCEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHSIL12.
  • CV301
  • MSB0011359C
  • N-803
  • NHS-IL12

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. 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 (GFR can also be used in place of
             creatinine or 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. Patients serologically positive for HIV, Hep B, Hep C are eligible as long as the
             viral loads are undetectable by quantitative PCR. HIV positive patients must have 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.

        EXCLUSION CRITERIA:

          1. Patients 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
             patient 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, patients
             may continue adjuvant hormonal therapy in the setting of a definitively treated cancer
             (e.g. breast).

          2. Patients 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 patients must have repeat CNS imaging at least a month after definitive
             treatment showing stable CNS disease. Patients with evidence of intratumoral 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. 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 CLL).

         10. Subjects with a known severe hypersensitivity reaction to a monoclonal antibody (grade
             >= 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to
             enrollment.

         11. Receipt of any organ transplantation requiring ongoing immunosuppression.

         12. Receipt of prior lymphodepleting chemotherapy (e.g. cyclophosphamide or fludarabine at
             standard lymphodepleting doses).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:ORR for Triple Therapy
Time Frame:one year
Safety Issue:
Description:To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) CEA/ MUC1 vaccines, (2) ALT-803 and (3) M7824 in subjects with advanced small bowel and colorectal cancers.

Secondary Outcome Measures

Measure:Safety of Triple Therapy
Time Frame:one year
Safety Issue:
Description:To evaluate the safety of the combination of (1) CV301, (2) N-803 and (3) M7824 in subjects with advanced small bowel and colorectal cancers.
Measure:Safety of Quadruple Therapy
Time Frame:one year
Safety Issue:
Description:To evaluate the safety of the combination of (1) CV301, (2) N-803, (3) M7824 and (4) NHS-IL12 in subjects with advanced small bowel and colorectal cancers.
Measure:PFS
Time Frame:study end
Safety Issue:
Description:To assess progression-free survival time (PFS) according to RECIST 1.1 per treatment assignment (three or four drug combination).
Measure:Overall Survival
Time Frame:study end
Safety Issue:
Description:To assess overall survival (OS) per treatment assignment (three or four drug combination).
Measure:Duration of Response
Time Frame:study end
Safety Issue:
Description:To assess duration of response per treatment assignment (three or four drug combination).
Measure:Hospitalization Due to PD AEs
Time Frame:study end
Safety Issue:
Description:To assess ratio of patients that are hospitalized because of adverse events attributed to disease progression

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • CEA MUC1 Vaccine
  • CV301
  • M7824
  • N-803
  • NHS-IL12

Last Updated

July 29, 2020