Description:
Background:
Often, metastatic human papillomavirus (HPV) associated cancers cannot be cured. They also do
not respond well to treatment. Some forms of colon cancer also have poor responses to
treatment. Researchers want to see if a new drug treatment can help people with these types
of cancers.
Objective:
To find a safe dose of entinostat in combination with NHS-IL12 and bintrafusp alfa and to see
if this treatment will cause tumors to shrink.
Eligibility:
Adults ages 18 and older who have cervical, oropharyngeal, anal, vulvar, vaginal, penile,
squamous cell rectal, or another cancer that may be associated with HPV infection or
microsatellite stable small bowel or colorectal cancer.
Design:
Participants will be screened with a medical history and physical exam. Their ability to do
daily activities will be assessed. They may have imaging scans of the brain and/or chest,
abdomen, and pelvis. They may have nuclear bone scans. They will have an electrocardiogram to
test heart function. They will have blood and urine tests. They may have a tumor biopsy.
Participants with skin lesions may have them photographed.
Some screening tests will be repeated during the study.
Treatment will be done in 28-day cycles. Participants will get bintrafusp alfa through an
intravenous catheter every 2 weeks. They will get NHS-IL12 as an injection under the skin
every 4 weeks. They will take entinostat by mouth once a week. They will complete a medicine
diary.
Participants will get treatment for 2 years. They will have 1-2 follow-up visits in the 30
days after treatment ends. Then they will be contacted every 6 months to check on their
health.
Title
- Brief Title: Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients With Advanced Cancer
- Official Title: Phase I/II Trial of the Combination of Bintrafusp Alfa (M7824), Entinostat and NHS-IL12 (M9241) in Patients With Advanced Cancer
Clinical Trial IDs
- ORG STUDY ID:
210007
- SECONDARY ID:
21-C-0007
- NCT ID:
NCT04708470
Conditions
- Cancer
- Solid Tumor
- Metastatic Checkpoint Refractory HPV Associated Malignancies
- Microsatellite Stable Colon Cancer (MSS)
Interventions
Drug | Synonyms | Arms |
---|
Bintrafusp Alfa | | 1/Arm 1 |
NHS-IL12 | | 1/Arm 1 |
Entinostat | | 1/Arm 1 |
Purpose
Background:
- Although PD-1(L1) inhibitors have been approved for the treatment of over a dozen
different tumor types in recent years, the majority of patients with advanced cancer
still do not respond to these agents, including patients with microsatellite stable
(MSS) colon cancer and patients with checkpoint refractory cancers (e.g., oropharyngeal,
cervical).
- Clinical studies suggest that treatment with a bifunctional fusion protein targeting
PD-L1 and TGF beta (bintrafusp alfa) may help overcome resistance or refractoriness to
anti PD-1(L1) therapy alone.
- Preclinical and clinical studies suggest that treatment with a histone deacetylase
inhibitor (HDAC inhibitor) concomitantly with anti PD-1(L1) therapy is safe and may help
overcome resistance or refractoriness to anti PD-1(L1) therapy alone.
- Preclinical and clinical studies suggest that treatment with a tumor targeted
immunocytokine (NHS-IL12) concomitantly with anti PD-1(L1) therapy is safe and may help
overcome resistance or refractoriness to anti PD-1(L1) therapy alone.
- Preclinical studies suggest that the use of a combination of multiple immunotherapy
agents may have improved anti-tumor efficacy.
- Specifically, preclinical studies have shown that the combination of three immunotherapy
agents (1) an HDAC inhibitor, entinostat (2) a tumor targeted immunocytokine (NHS-IL12),
and (3) a bifunctional fusion protein targeting PD-L1 and TGF beta (bintrafusp alfa)
produces greater anti-tumor activity than single or dual combinations of these agents.
Objectives:
- Phase I: To determine the recommended phase II dose (RP2D) of entinostat in combination
with NHS-IL12 and bintrafusp alfa.
- Phase II: To evaluate the objective response rate (ORR) (PR+CR) according to Response
Evaluation Criteria (RECIST 1.1) of the combination of entinostat, NHS-IL12, and
bintrafusp alfa in two separate populations:
- Checkpoint refractory human papillomavirus (HPV) associated malignancies;
- MSS small bowel or colorectal cancer.
Eligibility:
- Age >= 18 years old.
- Phase I: Subjects with cytologically or histologically confirmed locally advanced or
metastatic solid tumor (Cohort 1).
- Phase II: Subjects with cytologically or histologically confirmed locally advanced or
metastatic checkpoint refractory HPV associated malignancies (Cohort 2), or MSS small
bowel or colorectal cancer (Cohort 3)
- Patients with checkpoint refractory HPV associated malignancies (Cohort 2) must have
progressed on prior anti PD-1(L1) therapy. Patients in Cohort 1 and Cohort 3 can be
checkpoint na(SqrRoot) ve or check point refractory.
- Prior first line systemic therapy is required unless the patient declines standard
treatment after appropriate counseling has been provided.
- Subjects must have measurable disease per RECIST 1.1.
Design:
- This is a phase I/II trial of combination immunotherapy.
- All participants will be treated with a week lead in of entinostat alone followed by the
combination of entinostat, NHS-IL12 and bintrafusp alfa.
- Phase I (Arm 1) will be conducted using dose escalation/de-escalation of entinostat,
with fixed doses of NHS-IL12 and bintrafusp alfa in Cohort 1 (up to 18 total).
- Once the combination of all three agents has been determined to be safe, patients from
Cohort 2 and Cohort 3 may enroll into Phase II.
- Phase II: (Arm 2) will be conducted using a Simon optimal two-stage design.
- Cohort 2 (checkpoint refractory HPV associated malignancies, 16 total) and cohort 3 (MSS
small bowel or colorectal cancer, 16 total) patients will each be enrolled to Arm 2.
- If one or more out of twelve patients in a given cohort (2 or 3) has an objective
response, accrual will be expanded to enroll 16 evaluable patients on that cohort.
- If 3 or more of 16 (18.8%) patients respond in a given cohort-arm combination, that
would be sufficiently interesting to warrant further study of the combination in later
trials in that disease type.
Detailed Description
Background:
- Although PD-1(L1) inhibitors have been approved for the treatment of over a dozen
different tumor types in recent years, the majority of patients with advanced cancer
still do not respond to these agents, including patients with microsatellite stable
(MSS) colon cancer and patients with checkpoint refractory cancers (e.g., oropharyngeal,
cervical).
- Clinical studies suggest that treatment with a bifunctional fusion protein targeting
PD-L1 and TGF beta (bintrafusp alfa) may help overcome resistance or refractoriness to
anti PD-1(L1) therapy alone.
- Preclinical and clinical studies suggest that treatment with a histone deacetylase
inhibitor (HDAC inhibitor) concomitantly with anti PD-1(L1) therapy is safe and may help
overcome resistance or refractoriness to anti PD-1(L1) therapy alone.
- Preclinical and clinical studies suggest that treatment with a tumor targeted
immunocytokine (NHS-IL12) concomitantly with anti PD-1(L1) therapy is safe and may help
overcome resistance or refractoriness to anti PD-1(L1) therapy alone.
- Preclinical studies suggest that the use of a combination of multiple immunotherapy
agents may have improved anti-tumor efficacy.
- Specifically, preclinical studies have shown that the combination of three immunotherapy
agents (1) an HDAC inhibitor, entinostat (2) a tumor targeted immunocytokine (NHS-IL12),
and (3) a bifunctional fusion protein targeting PD-L1 and TGF beta (bintrafusp alfa)
produces greater anti-tumor activity than single or dual combinations of these agents.
Objectives:
- Phase I: To determine the recommended phase II dose (RP2D) of entinostat in combination
with NHS-IL12 and bintrafusp alfa.
- Phase II: To evaluate the objective response rate (ORR) (PR+CR) according to Response
Evaluation Criteria (RECIST 1.1) of the combination of entinostat, NHS-IL12, and
bintrafusp alfa in two separate populations:
- Checkpoint refractory human papillomavirus (HPV) associated malignancies;
- MSS small bowel or colorectal cancer.
Eligibility:
- Age >= 18 years old.
- Phase I: Subjects with cytologically or histologically confirmed locally advanced or
metastatic solid tumor (Cohort 1).
- Phase II: Subjects with cytologically or histologically confirmed locally advanced or
metastatic checkpoint refractory HPV associated malignancies (Cohort 2), or MSS small
bowel or colorectal cancer (Cohort 3)
- Patients with checkpoint refractory HPV associated malignancies (Cohort 2) must have
progressed on prior anti PD-1(L1) therapy. Patients in Cohort 1 and Cohort 3 can be
checkpoint na(SqrRoot) ve or check point refractory.
- Prior first line systemic therapy is required unless the patient declines standard
treatment after appropriate counseling has been provided.
- Subjects must have measurable disease per RECIST 1.1.
Design:
- This is a phase I/II trial of combination immunotherapy.
- All participants will be treated with a week lead in of entinostat alone followed by the
combination of entinostat, NHS-IL12 and bintrafusp alfa.
- Phase I (Arm 1) will be conducted using dose escalation/de-escalation of entinostat,
with fixed doses of NHS-IL12 and bintrafusp alfa in Cohort 1 (up to 18 total).
- Once the combination of all three agents has been determined to be safe, patients from
Cohort 2 and Cohort 3 may enroll into Phase II.
- Phase II: (Arm 2) will be conducted using a Simon optimal two-stage design.
- Cohort 2 (checkpoint refractory HPV associated malignancies, 16 total) and cohort 3 (MSS
small bowel or colorectal cancer, 16 total) patients will each be enrolled to Arm 2.
- If one or more out of twelve patients in a given cohort (2 or 3) has an objective
response, accrual will be expanded to enroll 16 evaluable patients on that cohort.
- If 3 or more of 16 (18.8%) patients respond in a given cohort-arm combination, that
would be sufficiently interesting to warrant further study of the combination in later
trials in that disease type.
Trial Arms
Name | Type | Description | Interventions |
---|
1/Arm 1 | Experimental | Dose escalation/de-escalation of entinostat, with fixed doses of NHS-IL12 and bintrafusp alfa | - Bintrafusp Alfa
- NHS-IL12
- Entinostat
|
2/Arm 2 | Experimental | RP2D of entinostat, NHS-IL12, and bintrafusp alfa | - Bintrafusp Alfa
- NHS-IL12
- Entinostat
|
Eligibility Criteria
-INCLUSION CRITERIA:
1. Phase I: Subjects with cytologically or histologically confirmed locally advanced or
metastatic solid tumor (Cohort 1).
2. Phase II: Subjects with cytologically or histologically confirmed locally advanced or
metastatic checkpoint refractory HPV associated malignancies (Cohort 2), or MSS small
bowel or colorectal cancer (Cohort 3).
- Cohort 2 includes:
- Cervical cancers;
- P16+ Oropharyngeal cancers;
- Anal cancers;
- Vulvar, vaginal, penile, and squamous cell rectal cancers;
- Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are
known HPV+.
3. Subjects must have received prior first line systemic therapy unless the patient is
not eligible to receive standard therapy or declines standard treatment after
appropriate counseling has been provided.
4. Patients with checkpoint refractory HPV associated malignancies (Cohort 2) must have
progressed on prior anti PD-1(L1) therapy. Patients in Cohort 1 and Cohort 3 can be
checkpoint na(SqrRoot) ve or check point refractory.
5. Subjects must have measurable disease, per RECIST 1.1.
6. Age >=18 years.
7. ECOG performance status < 2
8. Adequate hematologic function at screening, as follows:
- Absolute neutrophil count (ANC) >=1.5 x 10^9/L;
- Hemoglobin >= 9 g/dL;
- Platelets >= 100,000/microliter.
9. Adequate renal and hepatic function at screening, as follows:
- Measured or calculated creatinine clearance (using the Cockcroft-Gault equation)
> 50 mL/min
- 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).
10. The effects of the immunotherapies on the developing human fetus are unknown. For this
reason and because immunotherapeutic agents as well as other therapeutic agents used
in this trial are known to be teratogenic, women of child-bearing potential and men
must agree to use highly effective contraception (hormonal or barrier method of birth
control; abstinence) at the study entry and for 4 months after the last bintrafusp
alfa dose, 3 months after the last entinostat dose and 2 months after the last
NHS-IL12 dose, whichever occurs later. 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.
11. 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.
12. Subjects must be able to understand and be willing to sign a written informed consent
document.
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 enrollment except if the investigator has assessed that all residual
treatment-related toxicities have resolved or are at grade 1 severity and feel the
patient is otherwise suitable for enrollment.
2. Administration of live vaccine within 30 days prior to enrollment
3. Major surgery within 28 days prior to enrollment (minimally invasive procedures such
as diagnostic biopsies are permitted).
4. 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 CNS disease that has not progressed. Patients with CNS disease that
has not progressed at least a month after definitive treatment and continued on <=10
mg of prednisone (or equivalent) for treatment of brain or central nervous system
metastasis are eligible to enroll in this study. 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.
5. 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;
- 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;
6. Subjects on systemic intravenous or oral corticosteroid therapy with the exception of
hormone replacement or physiologic doses of corticosteroids (<= the equivalent of
prednisone 10 mg/day) or other immunosuppressive drugs 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.
7. 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 before enrollment) clinically significant bleeding events, or other illness or
medical condition considered by the Investigator as high risk for investigational drug
treatment.
8. Subjects with conditions associated with significant necrosis of nontumor-bearing
tissues: esophageal or gastroduodenal ulcers < 6 months prior to enrollment, organ
infarction < 6 months prior to enrollment, or active ischemic bowel disease.
9. Presence of medically significant third space fluid (symptomatic pericardial effusion,
ascites or pleural effusion requiring repetitive paracentesis).
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 compounds of similar
chemical or biologic composition to any of study drugs (grade >/= 3 NCI-CTCAE v5) will
be evaluated by the allergy/immunology team prior to enrollment.
12. 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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Objective response rate (ORR) of triple combination |
Time Frame: | two years |
Safety Issue: | |
Description: | Phase II: To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of entinostat, NHS-IL12, and bintrafusp alfa in two separate populations: checkpoint refractory HPV associated malignancies and MSS small bowel or colorectal cancer |
Secondary Outcome Measures
Measure: | Safety of Triple Combination Therapy |
Time Frame: | two years |
Safety Issue: | |
Description: | Phase II: To evaluate the safety of the combination of entinostat, NHS-IL12, and bintrafusp alfa in subjects with advanced malignancies |
Measure: | Progression-Free Survival (PFS) |
Time Frame: | two years |
Safety Issue: | |
Description: | Phase II: To assess progression-free survival (PFS), and duration of response (DoR) for each population (HPV, Colon) according to RECIST 1.1. |
Measure: | Duration of Response (DoR) |
Time Frame: | two years |
Safety Issue: | |
Description: | Phase II: To assess progression-free survival (PFS), and duration of response (DoR) for each population (HPV, Colon) according to RECIST 1.1. |
Measure: | Hospitalization due to AEs attributed to PD |
Time Frame: | two years |
Safety Issue: | |
Description: | Phase II: To assess duration of response and proportion of patients that are hospitalized because of adverse events attributed to disease progression. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Bintrafusp Alfa M7824
- Entinostat
- NHS-IL12 M9241
- PD-1(L1)
Last Updated
January 15, 2021