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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 : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE April 10, 2018
First Posted Date  ICMJE April 11, 2018
Last Update Posted Date October 19, 2020
Actual Study Start Date  ICMJE May 1, 2018
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 10, 2018)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2020)
  • Evaluate PFS in CRPC patients treated with BN-Brachyury + M7824 [ Time Frame: 6-month ]
    Progression free survival until progression or death without progression
  • Evaluate PFS in CRPC patients treated with BN-Brachyury + M7824 + ALT-803 [ Time Frame: 6-month ]
    Progression free survival until progression or death without progression
  • Evaluate PFS in CRPC patients treated with BN-Brachyury + M7824 + ALT-803 + Epacadostat [ Time Frame: 6-month ]
    Progression free survival until progression or death without progression
  • To characterize the safety profile of the above combinations and M7824 + ALT-803 [ Time Frame: 3 weeks DLT period ]
    Safety
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1)
Official Title  ICMJE A Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1)
Brief Summary

Background:

Immunotherapy drugs help the body to fight cancer. Scientists think that combining some of these drugs will make them work better than when used alone. This may be true for many types of cancer, including castration-resistant prostate cancer (CRPC).

Objective:

To test if the combination of the drugs BN-brachyury, M7824, ALT-803, and Epacadostat is safe and shrinks tumors.

Eligibility:

People ages 18 and older with CRPC or another metastatic cancer

Design:

Participants will be screened with:

  • Medical history
  • Physical exam
  • CT or MRI scans
  • Possible bone imaging
  • Blood, urine, and heart tests
  • Possible tumor biopsy

Participants will be treated with a 2-, 3- or 4-drug combinations of the following study drugs in 2-week cycles:

  • Participants will receive M7824 by IV once every 2 weeks.
  • Participants will receive ALT-803 by injection once every 2 weeks. They will record any skin changes at the injection site in a diary.
  • Participants will receive BN-brachyury as 4 injections to different limbs. They will get the first 3 doses 2 weeks apart. Then they will get doses every 4 weeks for 6 months, then every 3 months for 2 years, then every 6 months.
  • Participants will take Epacadostat orally every 12 hours. They will keep a pill diary.

Participants will have physical exams and blood and urine tests at the start of each cycle. They may have scans every 12 weeks.

Participants will continue treatment until their disease gets worse or they cannot tolerate the side effects.

Participants will have a follow-up visit 4-5 weeks after they stop treatment. They will have a physical exam and blood tests. They may be asked to return for scans every 3 months.

Detailed Description

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 castration resistant prostate cancer (CRPC) 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 CRPC, 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 CRPC:

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

Eligibility:

  • Adults with histologically proven CRPC, 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 2A, Arms 2.1A, 2.2BA. and 2.3 AC

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

Phase IIB: expansion with randomized enrollment into Cohorts 2D and 2R, Arms 2.1B, 2.2B. and 2.3B

  • Each Arm in Cohorts 2D and 2R: 2.1B, 2.2B and 2.3B 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 >= 30% sustained for > 21 days) in >= 2 patients is shown.
  • If only one arm is open for additional enrollment, patients will be directly assigned to this arm. If 2 arms are open for additional enrollment, patients will be randomized between these 2 open arms. If 3 arms are open for additional enrollment, patients will be randomized among these 3 open arms.

If there are >= 6 of 25 patients with a positive signal of activity in any expansion arm, that arm will be considered of interest for future studies.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Prostate Cancer
  • Prostate Cancer
  • Prostate Neoplasm
  • Advanced Solid Tumors
  • Solid Tumor
Intervention  ICMJE
  • Biological: M7824
    1,200 mg IV once every 2 weeks
  • Drug: ALT-803
    8-15 mcg/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
    600 mg orally twice daily (1200 total)
Study Arms  ICMJE
  • Experimental: Arm 1.1
    M7824 + ALT-803
    Interventions:
    • Biological: M7824
    • Drug: ALT-803
  • Experimental: Arm 2.1A
    M7824 + BN-Brachyury
    Interventions:
    • Biological: M7824
    • Biological: MVA-BN-Brachyury
    • Biological: FPV-Brachyury
  • Experimental: Arm 2.1B
    M7824 + BN-Brachyury
    Interventions:
    • Biological: M7824
    • Biological: MVA-BN-Brachyury
    • Biological: FPV-Brachyury
  • Experimental: Arm 2.2A
    M7824 + BN-Brachyury + ALT-803
    Interventions:
    • Biological: M7824
    • Drug: ALT-803
    • Biological: MVA-BN-Brachyury
    • Biological: FPV-Brachyury
  • Experimental: Arm 2.2B
    M7824 + BN-Brachyury + ALT-803
    Interventions:
    • Biological: M7824
    • Drug: ALT-803
    • Biological: MVA-BN-Brachyury
    • Biological: FPV-Brachyury
  • Experimental: Arm 2.3A
    M7824 + BN-Brachyury + ALT-803 + Epacadostat
    Interventions:
    • Biological: M7824
    • Drug: ALT-803
    • Biological: MVA-BN-Brachyury
    • Biological: FPV-Brachyury
    • Drug: Epacadostat
  • Experimental: Arm 2.3B
    M7824 + BN-Brachyury + ALT-803 + Epacadostat
    Interventions:
    • Biological: M7824
    • Drug: ALT-803
    • Biological: MVA-BN-Brachyury
    • Biological: FPV-Brachyury
    • Drug: Epacadostat
Publications * Redman JM, Steinberg SM, Gulley JL. Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer. J Immunother Cancer. 2018 Sep 18;6(1):91. doi: 10.1186/s40425-018-0409-8.

*   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: April 10, 2018)
113
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed any solid tumor (Cohort 1) or castration-resistant prostate cancer (CRPC, Cohorts 2A, 2D and 2R). No prior treatment other than testosterone lowering therapy for CRPC 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 adequate 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.

Prostate cancer 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. Patients with brain or CNS metastases enrolling to arm 1.1 are eligible if they are status post definitive radiotherapy or surgery, and are asymptomatic

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>170/ DBP>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 cytotoxic 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 3 months removed from treatment, with all treatment related toxicities resolving to at least grade 1.)

Patients who have 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

For Patients enrolling in Arm 2.3A and for patients who may be randomized to Arm 2.3B, the following additional exclusion critiera will apply:

  • Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or a drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before initiation of study therapy are excluded.
  • Since epacadostat s metabolism may be altered by drugs that inhibit UDP- glucuronosyltransferase UGT1A9 (see Appendix D), Patients receiving such drugs within 21 days of initiation of study therapy are excluded.
  • Subjects receiving coumarin-based anticoagulants (eg. Coumadin) are excluded.
  • Subjects having any history of Serotonin Syndrome (SS) after receiving serotonergic drugs are excluded.

    --Patients with a QTc interval > 480 milliseconds (B or F) at the screening are excluded. In the event that a single QTc (B or F) is > 480 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 480 milliseconds (for both the QTcB and QTcF). For subjects with an intraventricular conduction delay (QRS interval > 120 milliseconds), the JTc interval may be used in place of the QTc. The JTc must be < 340 milliseconds if JTc is used in place of the QTc. QTc prolongation due to pacemaker may enroll if the JTc is normal.

  • Subjects with left bundle branch block are excluded.
  • Pregnant women are excluded from this study because investigational agents used in this study (BN-Brachyury, M7824, ALT-803, and/or Epacadostat) could have 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 investigational agen s, breastfeeding should be discontinued if the mother is treated with either of them.
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: Michell J Manu, R.N. (240) 760-7117 michell.manu@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03493945
Other Study ID Numbers  ICMJE 180078
18-C-0078
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: James L Gulley, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 11, 2020

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