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.
To learn if a new combination of immunotherapy drugs can shrink tumors in people with
advanced small bowel and colorectal cancers.
People ages 18 and older who have advanced metastatic or refractory/recurrent small bowel
and/or colorectal cancer
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
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.
- 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
- 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
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
- 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.
- 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.
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
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.
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
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
- 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)
- 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
11. Receipt of any organ transplantation requiring ongoing immunosuppression.
12. Receipt of prior lymphodepleting chemotherapy (e.g. cyclophosphamide or fludarabine at
standard lymphodepleting doses).