Safety of Navoximod and NLG802 With Stereotactic Body Radiotherapy (SBRT) Treatment of Advanced Solid Tumors

NCT05469490 | Withdrawn Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: HCC 21-257
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This early phase trial proposes to study of stereotactic body radiation therapy (SBRT) with navoximod and NLG802, a prodrug of indoximod. Combinations of immune-oncology (IO) agents with complementary mechanisms as well as radiation represent a promising strategy to improve response rates to immunotherapy. Radiation therapy induces immunogenic cell death, increases production of tumor specific antigens, enhances TH cell functioning, and modulates immunosuppressive cell populations such as T regulatory cells and myeloid derived suppressor cells.

Conditions

Advanced Solid Tumors

Keywords

Stereotactic Body Radiotherapy (SBRT); immune-oncology (IO) agents; Indoleamine 2,3-dioxygenase 1 (IDO1)

Outcome Measures

Primary Outcomes (1)

• Recommended Phase 2 Dose (RP2D)

  The RP2D is determined by the occurrence of Dose-limiting Toxicities (DLT) defined as any Grade 3 or 4 toxicities to relevant organ systems determined to be possibly, likely or definitely related to treatment, deemed by the treating investigator that further administration of NLG802 and navoximod as not considered to be safe. Grade 3: Hold both NLG802 and navoximod until the AE recovers to Grade 0-1 or to pretreatment baseline level, whichever is more severe, and then resume treatment with NLG802 and navoximod at a dose level reduction. Clinically insignificant grade 3 events (ie - amylase/lipase) do not require drug hold Grade 4: Discontinue all study treatment permanently and withdraw patient from the study. Toxicity will be attributed to the combination of radiation with immunotherapy (as opposed to individual elements).If a dose reduction is required because of treatment-related toxicities, no dose re-escalation will be permitted for the duration of study treatment.

  Up to 90 days (patient)

Secondary Outcomes (6)

• Adverse Events (AE) and Serious Adverse Events (SAE)

  Up to 1 year (patient), up to 4 years (cohort)

• Objective response rate (ORR)

  Up to 1 year (patient), up to 4 years (cohort)

• Progression-free survival (PFS)

  Up to 4 years

• Overall survival (OS)

  Up to 4 years

• Local control per RECIST version 1.1

  Up to 4 years

Study Arms (1)

Stereotactic Body Radiotherapy (SBRT) + NLG802 and navoximod

EXPERIMENTAL

SBRT - Initial Starting Dose: Lung - Peripheral - 45 Gy (3 fractions) Lung - Central OR Mediastinal/Thoracic/Axillary/Cervical Lymph Node - 50 Gy (5 fractions) Liver - 45 Gy (3 fractions) Spinal/Paraspinal OR Osseous - 30 Gy (3 fractions) Abdominal/Pelvic (including Adrenal Gland) - 45 Gy (3 fractions) SBRT - Decreased DLT Dose: Lung - Peripheral - 42 Gy (3 fractions) Lung - Central OR Mediastinal/Thoracic/Axillary/Cervical Lymph Node - 47.5 Gy (5 fractions) Liver - 42 Gy (3 fractions) Spinal/Paraspinal OR Osseous - 27 Gy (3 fractions) Abdominal/Pelvic (including Adrenal Gland) - 42 Gy (3 fractions) NLG802 - 1452mg BID (no dose decrease) navoximod - Starting dose: 1000mg BID, Dose decrease 1: 800mg BID, Dose decrease 2: 600mg BID

Radiation: Stereotactic Body Radiotherapy (SBRT); Drug: navoximod; Drug: NLG802 (indoximod Prodrug)

Interventions

Stereotactic Body Radiotherapy (SBRT) RADIATION

SBRT is specialize radiation that is effective for ablating tumors at primary and metastatic locations that increases antigen uptake/processing/presentation.

Stereotactic Body Radiotherapy (SBRT) + NLG802 and navoximod

navoximod DRUG

A small molecule inhibitor with potent inhibition of IDO1 enzymatic activity as shown both in vitro and in vivo. As the main function of IDO1 is the regulation of acquired immune tolerance, and its expression in tumor- and dendritic cells in tumor draining lymph nodes negatively correlates with cancer prognosis and survival, navoximod-mediated IDO1 inhibition may restore immune reactivity towards tumors.

Also known as: (GDC-0919; previously NLG919)

Stereotactic Body Radiotherapy (SBRT) + NLG802 and navoximod

NLG802 (indoximod Prodrug) DRUG

An anti-tumor immunomodulator with the active ingredient of 1-methyl-D-tryptophan (NSC- 721782, 1-MT), which is an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway that increases the bioavailability of indoximod by leveraging existing mechanisms of absorption, increasing the exposure of indoximod.

Stereotactic Body Radiotherapy (SBRT) + NLG802 and navoximod

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed advanced solid tumor for which curative treatment is not available
• Undergone appropriate standard of care treatment options (in the opinion of the treating investigator).
• Evaluable disease by serum tumor marker or measurable disease as defined by RECIST Version 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
• Adequate organ function, as defined by the following:
• Absolute neutrophil count (ANC) ≥ 1,500/μL
• Platelets ≥ 100×10\^3/μL
• Hemoglobin ≥ 8 g/dL
• Serum creatinine ≤ 1.5× institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance (CrCL) \> 50 mL/min (creatinine clearance should be calculated per institutional standard). GFR can also be used in place of creatinine of CrCl.
• Serum total bilirubin ≤1.5× institutional ULN (except subjects with Gilbert's Syndrome, who must have normal direct bilirubin).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5× institutional ULN OR \< 5x ULN for subjects with liver metastases.
• Albumin \> 3.2 mg/dL.
• Participants may have had prior IO therapy (including but not limited to anti-CTLA4 and anti-PD1/L1) excluding prior IDO inhibitors
• Age and Reproductive Status
• Males and females ≥ 15 years of age at the time of informed consent.

You may not qualify if:

• Currently receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study Day 1 or have not recovered (i.e. \< grade 1 at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Prior chemotherapy, targeted small molecule therapy, radiation or other anti-cancer therapy (with exceptions for disease-specific hormone treatments considered standard of care) within 2 weeks prior to study Day 1 or have not recovered (i.e. \< grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: subjects with \< grade 2 neuropathy, endocrinopathy which is adequately controlled with hormone replacement therapy are an exception to this criterion and may qualify for the study.
• Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Symptomatic or clinically relevant active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patients with asymptomatic brain lesions deemed clinically irrelevant by the treating investigator are allowed.
• Prior radiation therapy (defined as \>10% of prior prescription dose) to the area planning to be treated with radiation.
• Diagnosis of immunodeficiency or are receiving systemic steroid therapy at a dose of \>10 mg prednisone daily or equivalent at time of first dose of trial treatment for another reason.
• Known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity or history of allergy to NLG802 and navoximod
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Known history of non-infectious pneumonitis that required steroids for treatment.
• Evidence of interstitial lung disease.
• Active infection requiring systemic therapy.
• History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Sponsors & Collaborators

• Luke, Jason, MD: lead
• Lumos Pharma: collaborator

MeSH Terms

Interventions

Radiosurgery; navoximod

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Adam Olson, MD, MS

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Assistant Professor of Medicine, Department of Radiation Oncology, UPMC Hillman Cancer Center

Study Record Dates

• First Submitted: July 18, 2022
• First Posted: July 21, 2022
• Study Start: October 1, 2022
• Primary Completion: August 1, 2024
• Study Completion (Estimated): December 1, 2026
• Last Updated: September 30, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share