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Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1).

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ClinicalTrials.gov Identifier: NCT03493945
Recruitment Status : Recruiting
First Posted : April 11, 2018
Last Update Posted : June 1, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

  • PD-1/PD-L1 signaling appears to be a major inhibitor of activated T cell anti-tumor immune responses. The rapid, deep and durable responses seen in various malignancies with PD-1/PD-L1 targeted agents demonstrate that blockade of this axis is key to facilitating immune responses within the tumor microenvironment (TME).
  • Prostate cancer is poorly recognized by T cells. Lack of an immune response is one explanation for the lower response rates (<15%) observed with anti-PD-1/PD-L1 therapies for prostate cancer.
  • Increasing response rates will likely require therapeutic nullification of multiple immune deficits by combining immunotherapies that generate tumor-specific T cells (vaccine), dampen the inhibitory milieu of the TME, and enhance T and NK cell activity within the TME.
  • A quick efficacy seeking trial, utilizing sequential arms offers a means to identify signals of activity for combinations of immunotherapy, added sequentially, in metastatic castrate resistant prostate cancer (mCRPC) patients.
  • BN-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine designed to induce an enhanced immune response against brachyury, which is overexpressed in many solid tumor types, including prostate adenocarcinoma. BN-Brachyury collectively refers to the priming doses (MVA-BN-Brachyury) and the boost doses (FPV-Brachyury) of the vaccine platform.
  • M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF- beta) receptor type 2, a TGF-beta trap. M7824 can also mediate antibody-dependent cellular cytotoxicity in vitro.
  • ALT-803 is an IL-15/IL-15R alpha superagonist complex that can enhance NK cell mediated ADCC and T-cell cytotoxicity.
  • Synergistic anti-tumor effects have been observed in vitro when combining M7824 and ALT-803, and in vivo when combining these agents with tumor vaccine in animal models.
  • IDO1 is overexpressed in many solid tumors and can contribute to immune escape by tumor cells. INCB024360 (Epacadostat) is an IDO1 inhibitor under investigation in combination with different immunotherapies in treatment of various malignancies.
  • In treating of mCRPC, we hypothesize that these agents and their effects will be complementary. Tumor-specific T cells generated by vaccine may become more functional in a TME following treatment with M7824 and Epacadostat. ALT-803 can further enhance the activity of antigen-specific T cells as well as NK cells.

Objective:

-To determine if there is clinical benefit to any of a set of 3 possible treatments for patients with mCRPC:

  • BN-Brachyury + M7824
  • BN-Brachyury + M7824 + ALT-803
  • BN-Brachyury + M7824 + ALT-803 + Epacadostat

Eligibility:

  • Adults with histologically proven mCRPC, or metastatic solid tumor of any type for which there is no standard treatment or standard treatment has failed.
  • Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.
  • Patients with acquired immune defects, active systemic autoimmune disease, history of organ transplant, history of chronic infections, or history of active inflammatory bowel disease are excluded.

Design:

  • Open label Phase I/II trial with following randomization during the expansion. Phase I: Cohort 1, Arm 1.1

    --Up to 18 patients with any solid tumor will be enrolled in dose escalation Cohort 1 for treatment in Arm 1.1 (flat dose of M7824 + different dose levels of ALT-803).

  • Phase IIA: expansion with sequential enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

    • Concurrently with the enrollment to Arm 1.1, 13 patients with mCRPC will start enrollment in Cohort 2 for treatment in Arm 2.1 (M7824 + BN-Brachyury).
    • When safe dosing of ALT-803 is identified during Phase I, 13 patients have enrolled in arm 2.1 and the first 6 patients, treated in Arm 2.1, have met safety requirements, 13 patients with mCRPC will start enrollment in Cohort 2 for treatment in Arm 2.2 (M7824 + BN-Brachyury + ALT-803).
    • When 13 patients have enrolled in Arm 2.2 and the first 6 patients, treated in Arm 2.2, have met safety requirements, 13 patients with mCRPC will start enrollment in Cohort 2 for treatment in Arm 2.3 (M7824 + BN-Brachyury + ALT-803 + Epacadostat).
  • Phase IIB: expansion with randomized enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

    • Each Arm in Cohort 2: 2.1, 2.2 and 2.3 will be open for additional enrollment (25 evaluable patients total) when the initial 13 patients have accrued, safety requirements are meet and a positive signal (defined as Objective Response by RECIST 1.1 or sustained PSA decrease greater than or equal to 30% sustained for > 21 days) in greater than or equal to 2 patients is shown.
    • If only one arm i...

Condition or disease Intervention/treatment Phase
Metastatic Prostate Cancer Prostate Cancer Prostate Neoplasm Advanced Solid Tumors Solid Tumor Biological: M7824 Drug: ALT-803 Biological: MVA-BN-Brachyury Biological: FPV-Brachyury Drug: Epacadostat Phase 1 Phase 2

Expanded Access : National Cancer Institute (NCI) has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 113 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1)
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm 1.1
M7824 + ALT-803
Biological: M7824
1,200 mg IV once every 2 weeks

Drug: ALT-803
10-20 mkg/kg subcutaneous every 2 weeks

Experimental: Arm 2.1A
M7824 + BN-Brachyury
Biological: M7824
1,200 mg IV once every 2 weeks

Biological: MVA-BN-Brachyury
MVA-BN-Brachyury will be administered subcutaneously (2 doses 2 weeks apart).

Biological: FPV-Brachyury
FPV-Brachyury will be given 2 weeks after second dose of MVA- BN-Brachyury, then every 4 weeks until 6 months, then every 3 months for 2 years, then every 6 month.

Experimental: Arm 2.2A
M7824 + BN-Brachyury + ALT-803
Biological: M7824
1,200 mg IV once every 2 weeks

Drug: ALT-803
10-20 mkg/kg subcutaneous every 2 weeks

Biological: MVA-BN-Brachyury
MVA-BN-Brachyury will be administered subcutaneously (2 doses 2 weeks apart).

Biological: FPV-Brachyury
FPV-Brachyury will be given 2 weeks after second dose of MVA- BN-Brachyury, then every 4 weeks until 6 months, then every 3 months for 2 years, then every 6 month.

Experimental: Arm 2.3A
M7824 + BN-Brachyury + ALT-803 + Epacadostat
Biological: M7824
1,200 mg IV once every 2 weeks

Drug: ALT-803
10-20 mkg/kg subcutaneous every 2 weeks

Biological: MVA-BN-Brachyury
MVA-BN-Brachyury will be administered subcutaneously (2 doses 2 weeks apart).

Biological: FPV-Brachyury
FPV-Brachyury will be given 2 weeks after second dose of MVA- BN-Brachyury, then every 4 weeks until 6 months, then every 3 months for 2 years, then every 6 month.

Drug: Epacadostat
100 mg orally twice daily (200 total)

Experimental: Arm 2.1B
M7824 + BN-Brachyury
Biological: M7824
1,200 mg IV once every 2 weeks

Biological: MVA-BN-Brachyury
MVA-BN-Brachyury will be administered subcutaneously (2 doses 2 weeks apart).

Biological: FPV-Brachyury
FPV-Brachyury will be given 2 weeks after second dose of MVA- BN-Brachyury, then every 4 weeks until 6 months, then every 3 months for 2 years, then every 6 month.

Experimental: Arm 2.2B
M7824 + BN-Brachyury + ALT-803
Biological: M7824
1,200 mg IV once every 2 weeks

Drug: ALT-803
10-20 mkg/kg subcutaneous every 2 weeks

Biological: MVA-BN-Brachyury
MVA-BN-Brachyury will be administered subcutaneously (2 doses 2 weeks apart).

Biological: FPV-Brachyury
FPV-Brachyury will be given 2 weeks after second dose of MVA- BN-Brachyury, then every 4 weeks until 6 months, then every 3 months for 2 years, then every 6 month.

Experimental: Arm 2.3B
M7824 + BN-Brachyury + ALT-803 + Epacadostat
Biological: M7824
1,200 mg IV once every 2 weeks

Drug: ALT-803
10-20 mkg/kg subcutaneous every 2 weeks

Biological: MVA-BN-Brachyury
MVA-BN-Brachyury will be administered subcutaneously (2 doses 2 weeks apart).

Biological: FPV-Brachyury
FPV-Brachyury will be given 2 weeks after second dose of MVA- BN-Brachyury, then every 4 weeks until 6 months, then every 3 months for 2 years, then every 6 month.

Drug: Epacadostat
100 mg orally twice daily (200 total)




Primary Outcome Measures :
  1. To determine if there is clinical benefit to any of a set of 3 possibletreatments for patients with mCRPC. [ Time Frame: 2 years ]
    Best treatment combination for patients with mCRPC



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed any solid tumor (Cohort 1) or prostate cancer (Cohort 2). No prior treatment other than testosterone lowering therapy for mCRPC is required.

For the Cohort 1, eligible patients must have a histologically, cytologically or radiographically proven metastatic or locally advanced solid tumor of any type, for which there is no curative standard therapy or standard therapy has failed.

Castrate testosterone level (less than 50ng/dl or 1.7nmol /L). (Patients with a malignancy other than prostate cancer are excluded from this criterion).

Radiological confirmation of metastatic disease, or

Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone:

--Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer

OR

--PSA progression defined by sequence of rising values separated by greater than 1 week

(2 separate increasing values over a minimum of 1 ng/ml (PCWG3 PSA eligibility criteria). If patients had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal. For patients on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal. The requirement for a 4-6 week withdrawal period following discontinuation of flutamide, nilutamide or bicalutamide only applies to patients who have been on these drugs for at least the prior 6 months. For all other patients they must stop bicalutamide, nilutamide or flutamide the day prior to enrollment.

Asymptomatic or mildly symptomatic form prostate cancer; no use of regularly scheduled opiate analgesics for prostate cancer-related pain. (Patients with a malignancy other than prostate cancer are excluded from this criterion).

Patients must agree to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy.

(Patients with a malignancy other than prostate cancer are excluded from this criterion).

Age greater than or equal to 18 years.

ECOG performance status less than or equal to 1

Patients must have normal organ and marrow function as defined below:

  • Absolute neutrophil count greater than or equal to 1000/mcL
  • Platelets greater than or equal to 100,000/mcL
  • Hemoglobin greater than or equal to 9.0 g/dL
  • Total bilirubin within normal institutional limits; in patients with

Gilbert s, less than or equal to 3.0 mg/dL

  • AST (AGOT)/ALT (AGPT) less than or equal to 2.5X upper limit of normal. For subjects with liver involvement in their tumor, AST less than or equal to 3.5. (SqrRoot) ULN, ALT less than or equal to 3.5 (SqrRoot) ULN, and bilirubin less than or equal to 3.0 is acceptable
  • Creatinine within 1.5X upper limit of normal institutional limits

The effects of BN-Brachyury, M7824, ALT-803, and Epacadostat on the developing human fetus are unknown. For this reason, men and women must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study and maintain such contraception until 4 months following the last dose of any study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her partner s treating physician immediately.

Ability of subject to understand and the willingness to sign a written informed consent document.

Patients with successfully treated HCV are eligible if HCV viral load is undetectable.

EXCLUSION CRITERIA:

Patients who are immunocompromised as follows:

  • Human immunodeficiency virus positivity due to the potential for decreased tolerance, and potential to be at risk for severe side effects with immunotherapies. These concerns are relevant to all drugs, as drug-drug interactions among antiretrovirals and immunotherapies are yet uncharacterized.
  • Chronic administration (defined as daily or every other day for continued use greater than 14 days) of systemic corticosteroids or other immune suppressive drugs, within 28 days before treatment on study. Nasal, or inhaled steroid, topical steroid creams and eye drops for small body areas are allowed.
  • Patients who have undergone allogeneic peripheral stem cell transplantation, or solid organ transplantation requiring immunosuppression

    • Active autoimmune disease, except patients with type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current immunosuppression, or with other endocrine disorders on replacement hormones or are not excluded if the condition is well controlled.

Patients with a history of brain/leptomeningeal metastasis, since these patients have a very poor prognosis and immunotherapy may take time to lead to beneficial clinical effects.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents to be used in the cohort the subject will be enrolled into.

Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or tobramycin).

Any condition which, in the opinion of the investigator, would prevent full participation in this trial (including the long-term follow-up), or would interfere with the evaluation of the trial endpoints.

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 minimal and feel the patient is otherwise suitable for enrollment.

Uncontrolled intercurrent acute or chronic illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class I), hepatic disease, unstable angina pectoris, serious cardiac arrhythmia, requiring medication, uncontrolled hypertension (SBP greater than 170/ DBP greater than 105) or psychiatric illness/social situations within 12 months that would limit compliance with study requirements.

Use of herbal products that may decrease PSA levels (e.g. saw palmetto)

Patients who have had chemotherapy for metastatic castration-resistant prostate cancer within the past year. (Patients who have had docetaxel for metastatic castration sensitive per CHAARTED data may enroll as long as they did not have progressive disease while on docetaxel and are 6 months removed from treatment, with all treatment related toxicities resolving to at least grade 1.)

Patients who have received radiation therapy, radionuclide therapy or undergone major surgery within 4 weeks of enrollment. A biopsy will not preclude a patient from starting study.

Patients with a history of hepatitis B (HBV) are excluded due to potential risk for viral reactivation and resulting liver injury in persons with latent HBV


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03493945


Contacts
Contact: Michell J Manu, R.N. (240) 760-7117 michell.manu@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: James L Gulley, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03493945     History of Changes
Other Study ID Numbers: 180078
18-C-0078
First Posted: April 11, 2018    Key Record Dates
Last Update Posted: June 1, 2018
Last Verified: April 30, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Immunotherapy
Combined Treatment
PD-1/PD-L1
Tumor-Specific T Cells
Novel Cancer Vaccine

Additional relevant MeSH terms:
Neoplasms
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs