Phase 2 Study of Bintrafusp Alfa in Recurrent/Metastatic Olfactory Neuroblastoma (BARON).

• ClinicalTrials.gov Identifier: NCT05012098
• Recruitment Status: Recruiting
• First Posted: August 19, 2021
• Last Update Posted: January 25, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information

• First Submitted Date: August 18, 2021
• First Posted Date: August 19, 2021
• Last Update Posted Date: January 25, 2023
• Actual Study Start Date: June 21, 2022
• Estimated Primary Completion Date: August 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 18, 2021)

objective response rate (ORR) [ Time Frame: 1 year ]

The fraction of evaluable participants who experience a response will be reported along with a 95% two-sided confidence interval.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 18, 2021)

• safety and tolerability of M7824 [ Time Frame: study end ]
  The fraction of participants who experience a toxicity, by grade and type of toxicity; Overall safety will be assessed by descriptive analyses using frequencies of AEs by grade.
• Overall Survival (OS) [ Time Frame: study end ]
  The time from the date of first treatment to the date of death (any cause).
• Duration of Response (DOR) [ Time Frame: study end ]
  The time measurement for CR or PR (whichever is first recorded) until the first documented date of PD or death.
• Progression Free Survival (PFS) [ Time Frame: study end ]
  The time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 2 Study of Bintrafusp Alfa in Recurrent/Metastatic Olfactory Neuroblastoma (BARON).
• Official Title: Phase 2 Study of Bintrafusp Alfa in Recurrent/Metastatic Olfactory Neuroblastoma (BARON).

Brief Summary

Background:

Olfactory neuroblastoma (ONB) is a rare cancer of the nasal cavity. At diagnosis, it is usually locally advanced. It tends to spread to the neck. Sometimes it spreads to the lungs and bones. Researchers want to find a better way to treat it.

Objective:

To learn if giving immunotherapy drug bintrafusp alfa can help ONB shrink or disappear.

Eligibility:

People aged 18 years and older diagnosed with recurrent or metastatic ONB that has not responded to standard treatment.

Design:

Participants will be screened with a medical history, blood and urine tests, and physical exam. Their ability to perform their normal activities will be assessed. They will have an electrocardiogram to evaluate their heart. They will have imaging scans and/or a nuclear bone scan, as needed. For some scans, they may receive a contrast dye.

Some screening tests will be repeated during the study.

Participants will receive bintrafusp alfa once every 2 weeks for 26 doses. They will get it intravenously over 60 minutes. They may get other medicines to prevent side effects. They will complete health questionnaires. Visits will last 4-6 hours.

Participants may have optional tumor biopsies.

Participants will have an end of treatment visit within 7 days after they stop taking the study drug. About 28 days after treatment ends, they will have a safety visit. They will have follow-up visits every 3 months for the first year, then every 6 months for years 2-5, and then once a year after that for the rest of their life. If their disease progresses, they may be eligible for re-treatment with the study drug

Detailed Description

Background:

Olfactory neuroblastoma (ONB, also known as esthesioneuroblastoma), is a rare malignant neoplasm of the nasal cavity. At diagnosis, ONB is often locally advanced. It tends to invade locally and has high rates of regional spread to the neck, and distally to the lungs and bones. The 10-year survival rate for ONB is reported at 46%.

Standard of care treatment is surgical resection followed by adjuvant radiation. In advanced unresectable or metastatic cases, systemic chemotherapy is used off label, with agent selection based on published case series. Genomic profiling of ONB has not yet informed the utilization of an appropriate molecularly targeted treatment.

High PD-L1 expression by immunohistochemistry was shown in ONB tumor samples, providing a rationale for immune checkpoint blockade in ONB. In addition, high expression of transforming growth factor beta (TGF-beta) ligands has been identified in ONB, implying that additional benefit may be achieved by combination of checkpoint blockade with TGF-beta inhibition.

Bintrafusp alfa is a novel bifunctional fusion protein composed of a blocking monoclonal antibody against PD-L1 fused with the soluble extracellular domain of the human TGF-beta receptor II (TGF-betaRII), acting as a decoy target for TGF-beta. The safety profile of bintrafusp alfa in clinical trials to date has been shown to be manageable.

Objective:

To assess the objective response rate (ORR) to bintrafusp alfa in participants with recurrent/metastatic ONB, immune checkpoint-naive (CN)

Eligibility:

Participants must have histologically confirmed recurrent or metastatic ONB, not amenable to potentially curative local therapies.

Participants should have received at least one line of systemic therapy including a platinum agent, with evidence of disease progression clinically or radiographically.

Presence of >= 1 lesion measurable by RECIST 1.1 criteria

Age >= 18 years, men and women

Adequate organ function, and without serious comorbidity (e.g., autoimmune disease), that would preclude concurrent systemic treatment.

Design:

Single-institution, single-arm Phase II trial to determine ORR in participants with recurrent/metastatic ONB treated with bintrafusp alfa.

Participants will be treated with bintrafusp alfa 1200 mg every 2 weeks for 26 doses.

The trial will initially enroll 12 checkpoint-naive (CN) participants; if responses are observed in one or more participants, the second stage will enroll another 9 CN participants to define the response rate to bintrafusp alfa, for a total of 21 CN participants.

An additional cohort of checkpoint-resistant (CR) participants will be enrolled and evaluated separately. Initially 5 CR participants will be enrolled; if responses are observed in one or more participants, the second stage will enroll another 3 participants, for a total of up to 8 CR participants. Accrual for CR participants will end when the preset number of CN participants has been accrued.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Olfactory Neuroblastoma
• Esthesioneuroblastoma
• Neoplasm of the Nasal Cavity

Intervention

Drug: Bintrafusp alfa / M7824

Participants will be treated with bintrafusp alfa 1200 mg every 2 weeks for 26 doses.

Study Arms

Experimental: 1/Arm 1

Treatment with Bintrafusp alfa

Intervention: Drug: Bintrafusp alfa / M7824

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 18, 2021): 32
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: August 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

-INCLUSION CRITERIA:

1. Histologically or cytologically confirmed recurrent or metastatic ONB not amenable to potentially curative local therapies. Review of tissue samples by Pathology at the NIH is preferred.
2. Participants must have measurable disease, per RECIST 1.1. A previously treated lesion by radiotherapy can be chosen as the target lesion only if progression in the respective lesion has been demonstrated during or following radiotherapy.
3. Participants should have received at least one line of systemic therapy including a platinum agent, with evidence of disease progression clinically or radiographically.
4. Men or Women >=18 years of age on day of signing informed consent. Because no dosing or adverse event data are currently available on the use of bintrafusp alfa in participants <18 years of age, children are excluded from this study.
5. ECOG performance status (PS) =<2.

6. Participants must have adequate organ and marrow function as defined below:

   • Absolute neutrophil count (ANC) >=1,500/mcL
   • Hemoglobin<TAB>>=9 g/dL (transfusions allowed)
   • Platelets >=100,000/mcL
   • Serum Creatinine <= 1.5 (SqrRoot) ULN OR Measured CrCl or eGFR by CKD- EPI formula may be used to estimate CrCl/eGFR >=30 mL/min/1.73m^2 for participant with creatinine levels > 1.5 x institutional ULN
   • Serum total bilirubin <=1.5 x upper limit of normal (ULN) OR Direct bilirubin <=ULN for participants with total bilirubin levels >1.5 x ULN
   • AST(SGOT) and ALT(SGPT) <=2.5 (SqrRoot) ULN

7. The effects of immunotherapy on the developing human fetus are unknown. Therefore, participants must use effective methods of contraception (such as implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomized partner).

   • Women of child-bearing potential (WOCBP: any woman who has experienced menarche and has not had hysterectomy or bilateral oophorectomy or is not postmenopausal (amenorrheic 12 months or more following cessation of exogenous hormonal treatments; if <50 years old need follicle stimulating hormone FSH in the post-menopausal range)) must agree to use highly effective contraception prior to study entry and for up to 65 days following the last dose of study treatment.
   • Men must agree to use highly effective contraception prior to study entry and up to 125 days following the last dose of study treatment.
   • 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. Participants with bone metastases or hypercalcemia on intravenous bisphosphonate treatment, zolendronic acid, denosumab, or similar agents are eligible to participate and may continue this treatment.
9. Participants with treated CNS ONB lesions are eligible if follow-up brain imaging after at least a month following central nervous system (CNS)-directed therapy shows no evidence of progression.
10. Participants with new or progressive non-intraparenchymal CNS ONB lesions are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
11. Human immunodeficiency virus (HIV)-positive participants 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. For participants with serological evidence of chronic hepatitis B virus (HBV) infection, the HBV DNA viral load must be undetectable on suppressive therapy, if indicated.
13. For participants with serological evidence of HCV infection, the HCV RNA viral load must be negative to be eligible for study participation.
14. Ability of participant to understand and the willingness to sign a written informed consent document.

15. Must co-enroll in the following two studies. A separate inform consent will be obtained from participant for these studies.

    • 21-C-0009: A Natural History Study of Children and Adults with Olfactory Neuroblastoma, and
    • 18-DC-0051: Biospecimen procurement for NIDCD clinical protocols

EXCLUSION CRITERIA:

1. Anticancer treatment, concurrent or prior (chemotherapy, monoclonal antibody, cytokine therapy, immune therapy, targeted small molecule therapy) or any investigational drug, within 4 weeks or 5 half-lives (whichever shorter) prior to the first drug administration. All residual treatment-related toxicities must have resolved or be minimal and not constitute a safety risk. Note: Palliative radiotherapy is permitted concurrently or within the pretreatment period. Subjects receiving bisphosphonates or denosumab are eligible provided treatment was initiated at least 14 days before treatment.
2. Participants who received prior checkpoint blockade therapy and were taken off treatment for serious adverse events related to immuno-therapy are excluded.
3. Major surgery within 4 weeks prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).

4. Active or prior documented autoimmune or inflammatory diseases that might deteriorate on immunostimulatory agent (including colitis or Crohn s disease, systemic lupus erythematosus, sarcoidosis, vasculitis, Grave s disease, hypophysitis, uveitis, rheumatoid arthritis etc.), except the following:

   • Type I diabetes mellitus
   • Chronic skin conditions that do not require systemic therapy (including eczema, vitiligo, alopecia, psoriasis)
   • Hypothyroidism (e.g. post-Hashimoto thyroiditis) stable, on hormone replacement
   • Mild autoimmune disease not active in the last 5 years may be eligible after consultation with the principal investigator.

5. Current use of immunosuppressive medication within 14 days before the first dose of the study medication, except the following:

   • Intranasal, inhaled, topical glucocorticoids; locally injected glucocorticoids (i.e. intra-articular, intra-ocular)
   • Systemic glucocorticoids at physiologic doses (generally <= 10 mg prednisone or equivalent per day)
   • Glucocorticoids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study.

6. Uncontrolled intercurrent chronic or acute illness including, but not limited to the following, that may limit interpretation of results or increase risk to the participant in the judgment of the investigator:

   • Bleeding diathesis or recent (<3 months) clinically significant bleeding event.
   • Prior organ transplantation including allogenic stem-cell transplantation

   • Impaired cardiovascular function or clinically significant cardiovascular disease, including, but not limited to, any of the following:

     • cerebral vascular accident/stroke (< 3 months prior to enrollment),
     • acute coronary syndromes (including myocardial infarction < 6 months prior to enrollment, unstable angina),
     • Congestive Heart Failure (>= New York Heart Association Classification Class III); CHF Class II must have been stable for 3 months prior to enrollment
     • history or presence of clinically significant cardiac arrhythmia including resting bradycardia, uncontrolled atrial fibrillation or paroxysmal supraventricular tachycardia (controlled arrhythmias, e.g. stable atrial fibrillation, may be allowed at the discretion of the investigator),
     • history of myocarditis
   • History of idiopathic pulmonary fibrosis, drug-induced or idiopathic pneumonitis, active interstitial lung disease, blood oxygen saturation <90% at rest (on ambient air).
   • Clinically significant hepatic disease.
   • Active infection requiring systemic therapy (minor infections may be allowed at the discretion of the investigator).
7. Subjects unwilling to accept blood products as medically indicated.
8. Vaccination with live vaccines within 4 weeks of the first dose of treatment and while on study is prohibited. Inactivated vaccines may be administered.
9. History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to bintrafusp alfa. Participants with history of severe hypersensitivity reaction to monoclonal antibodies (grade >= 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to enrollment.
10. History of second malignancy within 3 years of enrollment except for the following: adequately treated localized basal cell or squamous skin cancer, cervical carcinoma in situ, superficial bladder cancer, other localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g. low risk CLL).
11. Pregnant or breastfeeding women are excluded from this study because the study medications 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 the study medications, breastfeeding should be discontinued if the mother is treated on this protocol.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Sheri A McMahon, R.N.; (240) 760-7968; sheri.mcmahon@nih.gov

Contact: Charalampos Floudas, M.D.; (240) 858-3032; charalampos.floudas@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05012098
• Other Study ID Numbers: 10000030; 000030-C
• 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

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Charalampos Floudas, M.D.; National Cancer Institute (NCI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: January 23, 2023