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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04491955
Recruitment Status : Recruiting
First Posted : July 30, 2020
Last Update Posted : November 30, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE July 29, 2020
First Posted Date  ICMJE July 30, 2020
Last Update Posted Date November 30, 2020
Actual Study Start Date  ICMJE September 22, 2020
Estimated Primary Completion Date July 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 29, 2020)
  • ORR for Triple Therapy [ Time Frame: one year ]
    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.
  • ORR for Quadruple Therapy [ Time Frame: one year ]
    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, (3) M7824 and (4) NHS-IL12 in subjects with advanced small bowel and colorectal cancers.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 29, 2020)
  • Safety of Triple Therapy [ Time Frame: one year ]
    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.
  • Safety of Quadruple Therapy [ Time Frame: one year ]
    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.
  • PFS [ Time Frame: study end ]
    To assess progression-free survival time (PFS) according to RECIST 1.1 per treatment assignment (three or four drug combination).
  • Overall Survival [ Time Frame: study end ]
    To assess overall survival (OS) per treatment assignment (three or four drug combination).
  • Duration of Response [ Time Frame: study end ]
    To assess duration of response per treatment assignment (three or four drug combination).
  • Hospitalization Due to PD AEs [ Time Frame: study end ]
    To assess ratio of patients that are hospitalized because of adverse events attributed to disease progression
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers
Official Title  ICMJE Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers
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 (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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Small Bowel Cancers
  • Colorectal Cancers
Intervention  ICMJE
  • Biological: CV301
    CV301 vaccine consists of MVA-BNCV301 and FPVCV301. MVA-BNCV301 (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.
  • Drug: MSB0011359C
    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 independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.
  • Drug: N-803
    N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every two weeks on Arm 1 and every 4 weeks on Arms 2A and 2B.
  • Drug: NHS-IL12
    NHS-IL12 will be administered at as dose of 8, 12 or 16.8 microgram/kg by SC injection every 4 weeks on Arm 2A and Arm 2B according to the dose escalation schema, and the MTD or highest dose identified.
Study Arms  ICMJE
  • Experimental: 1/Arm 1
    CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).
    Interventions:
    • Biological: CV301
    • Drug: MSB0011359C
    • Drug: N-803
  • Experimental: 2/Arm 2A
    CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHSIL12.
    Interventions:
    • Biological: CV301
    • Drug: MSB0011359C
    • Drug: N-803
    • Drug: NHS-IL12
  • Experimental: 3/Arm 2B
    CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHSIL12.
    Interventions:
    • Biological: CV301
    • Drug: MSB0011359C
    • Drug: N-803
    • Drug: NHS-IL12
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 29, 2020)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2024
Estimated Primary Completion Date July 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

-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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Elizabeth A Lamping (240) 760-6083 elizabeth.lamping@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04491955
Other Study ID Numbers  ICMJE 200138
20-C-0138
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Julius Y Strauss, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date November 24, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP