NTX-301 Monotherapy in Advanced Solid Tumours and in Combination With Platinum-based Chemotherapy in Advanced Ovarian & Bladder Cancer and in Combination With Temozolomide in High-grade Glioma

NCT04851834 | Terminated Phase 1 FDA Drug

• 1 other identifier: XNTR-20-02
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

This is a Phase 1/2, open-label, dose-exploration, combination/expansion study, which will start by evaluating the safety and tolerability of NTX-301, an oral DNMT1 inhibitor, as a monotherapy in patients with advanced solid tumours, who have failed treatment with available therapies known to be active for treatment of their corresponding disease. It will then explore the safety and tolerability of NTX-301 in combination with platinum-based therapy in patients with ovarian and bladder cancer. Optionally, the safety and tolerability of NTX-301 in combination with Temozolomide (TMZ) in patients with Isocitrate Dehydrogenase 1 (IDH1) mutated high-grade glioma will also be assessed.

Conditions

Advanced Solid Tumor; Platinum-Resistant Ovarian Cancer; Platinum-Resistant Urothelial Carcinoma; High-grade Glioma

Keywords

Hypomethylating Agent; Nucleoside Analog; DNA Demethylation; Solid Tumors; Ovarian Neoplasms; Urinary Bladder Neoplasms; Platinum-resistant; Carboplatin; Cisplatin; Glioma; IDH1; Temozolomide

Outcome Measures

Primary Outcomes (2)

• Safety & Tolerability: Incidence, type, and severity of Adverse Events (AE)

  15 Months

• Safety & Tolerability: Dose-limiting Toxicities (DLT)

  15 Months

Secondary Outcomes (6)

• Incidence of DLTs according to the MTD/RP2D evaluation process

  12 Months

• Pharmacokinetics (PK): Maximum observed concentration (Cmax)

  12 Months

• Pharmacokinetics (PK): Time to Cmax (Tmax)

  12 Months

• Pharmacokinetics (PK): Trough concentrations

  12 Months

• Pharmacokinetics (PK): Area under the concentration-time curve (AUC0-t)

  12 Months

Other Outcomes (8)

• Tumour Response Assessment per RECIST 1.1 &/or RANO criteria

  Up to 32 Months

• Efficacy: Objective response rate (ORR)

  Up to 32 Months

• Efficacy: Disease control rate (DCR)

  Up to 32 Months

Study Arms (5)

NTX-301 Monotherapy Dose Escalation

EXPERIMENTAL

NTX-301 monotherapy dose escalation in patients with advanced solid tumours

Drug: NTX-301

NTX-301 platinum-based doublet therapy Dose Escalation

EXPERIMENTAL

NTX-301 combined with platinum-based chemotherapy in platinum-resistant advanced ovarian \& bladder cancer

Drug: NTX-301; Drug: Platinum-based Chemotherapy

NTX-301 platinum-based doublet therapy Dose Expansion

EXPERIMENTAL

NTX-301 combined with platinum-based chemotherapy in platinum-resistant advanced ovarian \& bladder cancer

Drug: NTX-301; Drug: Platinum-based Chemotherapy

NTX-301 Temozolomide doublet therapy Dose Escalation

EXPERIMENTAL

NTX-301 combined with Temozolomide (TMZ) as adjuvant (maintenance) treatment in IDH1 mutated high-grade glioma

Drug: NTX-301; Drug: Temozolomide

NTX-301 Temozolomide doublet therapy Dose Expansion

EXPERIMENTAL

NTX-301 combined with Temozolomide (TMZ) as adjuvant (maintenance) treatment in IDH1 mutated high-grade glioma

Drug: NTX-301; Drug: Temozolomide

Interventions

NTX-301 DRUG

Oral hypomethylating agent

NTX-301 Monotherapy Dose Escalation; NTX-301 Temozolomide doublet therapy Dose Escalation; NTX-301 Temozolomide doublet therapy Dose Expansion; NTX-301 platinum-based doublet therapy Dose Escalation; NTX-301 platinum-based doublet therapy Dose Expansion

Platinum-based Chemotherapy DRUG

Standard of care for ovarian and bladder cancer

Also known as: Cisplatin, Carboplatin

NTX-301 platinum-based doublet therapy Dose Escalation; NTX-301 platinum-based doublet therapy Dose Expansion

Temozolomide DRUG

Standard of care for high-grade glioma

NTX-301 Temozolomide doublet therapy Dose Escalation; NTX-301 Temozolomide doublet therapy Dose Expansion

Eligibility Criteria

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

You may qualify if:

• Ability to understand and be willing to sign an informed consent form.
• Male or female, ≥ 18 years old at the time of screening.
• Diagnosis of histologically or cytologically confirmed:
• Locally advanced or metastatic cancer (all solid tumours). Subjects must be considered refractory or intolerant to SOC therapies or have refused standard therapy. If the last treatment a subject received was an inhibitor of DNA synthesis or a hypomethylating agent, at least 5 half-lives must have passed prior to commencing treatment. (Phase 1a, Dose Escalation Monotherapy), OR
• Locally advanced or metastatic cancer (ovarian or bladder cancer and other solid tumours where in the opinion of the investigator, retreatment with cisplatin or carboplatin may be beneficial to the subject). Subjects must be considered refractory or intolerant to SOC therapies or have refused standard therapy, in such a case, reason for the refusal to be captured in Case Report Form (CRF). If subject is having a drug holiday to recover from cisplatin toxicity, entry to the trial is allowed if the PI feels the subject will receive further benefit from cisplatin, the toxicity has recovered to ≤ CTCAE Grade 1 and all other eligibility criteria are met. Last treatment prior to trial entry with a platinum is not required. If the last treatment a subject received was an inhibitor of DNA synthesis or a hypomethylating agent, at least 5 half-lives must have passed prior to commencing study treatment). (Phase 1b, Dose \& Disease Expansion Combination Arms, Arms 1 \& 2), OR
• High-grade glioma, such as glioblastoma multiforme (GBM) that are:
• Newly diagnosed and are undergoing, or are planned to undergo, 42 Days of SOC chemoradiation therapy as per part 1 of the eviQ protocol 3364 v.1. Subjects successfully enrolled will receive a subsequent combination of NTX-301, Days 1-5 and 8-12 as well Temozolomide on Days 15-19 of their first 28-Day cycle of part 2 of the eviQ protocol 3364 v.1. This combination arm replaces the Temozolomide monotherapy SOC maintenance therapy as described in Part 2 of the eviQ protocol 3364 v.1. In order to prevent any potential delays after radiotherapy, subjects can be enrolled at any time during Chemoradiation (eviQ Part 1). In order to commence the TMZ combination arms the subject is required to complete the full 42 Days of eviQ part 1, and also receive their first dose of the TMZ combination arm within the screening window. This timing can be adjusted based on medical need on a subject-by-subject basis as per the discretion of the principal investigator together with the approval of the medical monitor (Phase 1b, 2a, Dose \& Disease Expansion Combination GBM (optional) Arm, Arms 3 \& 4) Note: subjects must also have at least one measurable disease lesion per RECIST 1.1 \&/or RANO criteria. For Phase 1a only, non-measurable disease may also be included based on PI and MM discretion on a case-by-case basis.
• Eastern Cooperative Oncology Group performance status of 0 to 1
• Able to take oral medications and willing to record daily adherence to the study drug.
• Cardiac
• QT interval corrected using the Fridericia method (QTcF) ≤ 450 msec for males and ≤ 470 msec for females at screening and on Day 1, prior to dose administration (the mean of triplicate measurements will be used to determine eligibility)
• LVEF \>45% based on ECHO Scan within 60 Days of screening.
• Evidence of adequate hepatic function at screening, as defined by the following:
• AST and ALT ≤2.5 × upper limit of normal (ULN) (≤5 × ULN if liver metastases are present); and
• Total bilirubin ≤1.5 × ULN (\< 2.0 x ULN for subjects with liver metastases or documented Gilbert's syndrome).

You may not qualify if:

• Investigational agents, including hypomethylating agents, in the past 5 half-lives
• Patients with symptomatic brain metastases.
• Evidence of abnormal cardiac function as defined by any of the following:
• Myocardial infarction within 6 months of Cycle 1, Day 1
• Symptomatic congestive heart failure (New York Heart Association \> class II)
• Unstable angina
• Unstable cardiac arrhythmia. Stable cardiac arrhythmia that is Medically managed is allowable. Borderline subjects are allowable on a case-by-case basis as per the discretion of the Principal Investigator and approval by the Medical Monitor and Sponsor.
• Unable to swallow oral medications.
• Gastrointestinal (GI) Gastrointestinal conditions that, in the opinion of the Investigator, could affect the absorption of NTX-301
• History of bowel obstruction, abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of the first administration of NTX-301 (Cycle 1, Day 1) (unless otherwise approved by the Investigator).
• Unless approved by treating physician, use of any herbal or prescription medications, or consumption of foods known to be strong inhibitors of cytochrome P450 3A (CYP3A) enzymes within 7 Days prior to the first administration of NTX-301 (Cycle 1, Day 1). These include (but are not limited to):
• Certain Medications defined within the study protocol
• Foods: Grapefruit or Seville orange (or grapefruit- or Seville orange-containing products, including juices).
• Use of any herbal or prescription medications known to be strong inducers of CYP3A enzymes within 7 Days prior to the first administration of NTX-301 (Cycle 1, Day 1)
• Clinically significant active infection within 2 weeks of the first dose of NTX-301 (Cycle 1, Day 1).

Sponsors & Collaborators

• Xennials Therapeutics Australia Pty Ltd: lead
• Pinotbio, Inc.: collaborator

Study Sites (2)

St. Vincent's Hospital - The Kinghorn Cancer Center

Darlinghurst, New South Wales, 2010, Australia

Location

St. George Private Hospital

Kogarah, New South Wales, 2217, Australia

Location

MeSH Terms

Conditions

Glioma; Ovarian Neoplasms; Urinary Bladder Neoplasms

Interventions

Platinum Compounds; Cisplatin; Carboplatin; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Urologic Neoplasms; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Organic Chemicals; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Joyce L. Steinberg, MD

  Xennials Therapeutics Inc

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Dose escalation to determine MTD/RP2D, then dose expansion

Study Record Dates

• First Submitted: April 8, 2021
• First Posted: April 20, 2021
• Study Start: August 25, 2021
• Primary Completion: November 8, 2022
• Study Completion: November 8, 2022
• Last Updated: December 20, 2022

Record last verified: 2022-12

Locations

AU (2)