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Advanced Solid TumorPhase 1/2NCT04851834

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

A Phase 1/2 study testing NTX-301, Platinum-based Chemotherapy and Temozolomide in people with Advanced Solid Tumor and Platinum-Resistant Ovarian Cancer, run by Xennials Therapeutics Australia Pty Ltd at 2 sites in Australia.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
NTX-301, Platinum-based Chemotherapy and Temozolomide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
2 sitesAustralia
Study dates
25 Aug 2021to 8 Nov 2022
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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).
  • Adequate haematology laboratory assessment at screening, as defined by:
  • Absolute neutrophil count ≥1.00 x109/L;
  • Haemoglobin ≥90 g/L; and
  • Platelet count ≥100 x109/L.
  • Evidence of adequate renal function, as defined by a calculated creatinine clearance ≥45 mL/min using the Cockcroft-Gault equation, renal nuclear medical scan, or a 24-hour urine collection with plasma and urine creatinine concentrations respectively. There can be exceptions on a case-by-case basis as per the discretion of the principal investigator and approval by the Medical Monitor and Sponsor.
  • Adequate coagulation laboratory assessments (i.e., within normal reference range values) at screening, in the opinion of the Investigator.
  • Female subjects must:
  • Be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the Screening visit) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone level consistent with postmenopausal status, per local laboratory guidelines), or
  • If of child-bearing potential, must agree not to attempt to become pregnant, must not donate ova, and, if engaging in sexual intercourse with a male partner, must agree to use an acceptable method(s) of contraception from signing the consent form until at least 45 Days after the last dose of study drug.
  • Male subjects must agree not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception from signing the consent form until at least 90 Days after the last dose of study drug
  • Estimated life expectancy of at least 3 months, in the opinion of the Investigator.
  • Willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures.
  • Willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures.

Who cannot join

  • 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
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  • 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).
  • Positive test results for active human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the Screening visit.
  • History of other malignancy within the past 2 years, with the following exceptions:
  • Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrolment and felt to be at low risk for recurrence by the treating physician.
  • Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease.
  • Adequately treated cervical carcinoma in situ without evidence of disease.
  • Adequately treated breast ductal carcinoma in situ without evidence of disease.
  • Prostatic intraepithelial neoplasia without evidence of prostate cancer.
  • Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ.
  • Major surgery within 28 Days of Cycle 1, Day1, with the following exceptions:
  • Major surgical procedures ≤28 Days of beginning study drug, or
  • Minor surgical procedures ≤7 Days.
  • No waiting required following port-a-cath placement or for venous access.
  • Planned elective surgery unrelated to the subject's oncologic diagnosis, such as hernia repair, may be allowed, at the discretion of the Investigator, as long as it was performed at least 2 weeks prior to starting NTX-301, and the subject has recovered fully from this procedure.
  • Received cancer-directed therapy within the following timeframes:
  • Anti-tumour therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy or investigational agent) within 28 Days or (unless 5 times the half-life is shorter than 28 Days); Note: concurrent use of hormone deprivation therapy for hormone-refractory prostate cancer, bisphosphonate or denosumab for skeletal related events per institution guideline is permitted.
  • Wide field radiation administered ≤28 Days or limited field radiation for palliation ≤7 Days prior to starting study drug or has not recovered from side effects of radiation therapy.
  • Receiving treatment with any other concurrent investigational device(s) or conventional agent(s) within 28 Days (unless 5 times the half-life is shorter than 28 Days) of Cycle 1, Day 1.
  • Adverse Events due to investigational or conventional agents >4 weeks earlier that have not recovered to a severity of Grade 0 or Grade 1 (per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 or higher), with the exception of alopecia.
  • Note: (applies to Phase 1a, dose levels 3-5 and Phase 1b only):
  • Subjects with chronic Grade 2 toxicities may be eligible per discretion of the Investigator and Sponsor (e.g., Grade 2 chemotherapy induced neuropathy).
  • Grade 2 or 3 toxicities from prior anti-tumour therapy that are considered irreversible - defined as having been present and stable for > 6 months (such as ifosfamide-related proteinuria) may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the Investigator and Sponsor
  • For women of childbearing potential, a positive pregnancy test at screening, or on Day 1, prior to dose administration.
  • Pregnant or breast-feeding (or planning to breastfeed while on study through 15 Days after the last dose of study drug.
  • Hypersensitivity or other clinically significant reaction to the study drug or its inactive ingredients.
  • Known substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
  • Any other condition or prior therapy that in the opinion of the Investigator would make the subject unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements
  • COVID-19 vaccinations: Administration of an approved COVID-19 vaccine less than14 Days prior to dosing.

Trial locations and contacts

2 sites in 1 country.

Australia2 sites

  • St. Vincent's Hospital - The Kinghorn Cancer Center

    Darlinghurst, New South Wales, 2010

  • St. George Private Hospital

    Kogarah, New South Wales, 2217

Other trials in Australia

About this study

Official title: A Phase 1/2, Open-label, Dose-exploration and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of NTX-301 Monotherapy in Advanced Solid Tumours, and in Combination With Platinum-based Chemotherapy in Advanced Ovarian & Bladder Cancer, and in Combination With Temozolomide as Adjuvant (Maintenance) Therapy in High-grade Glioma (Optional Arm)

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.

Read the detailed description

Dose Exploration (Phase 1a, n~25): This part of the study will assess the safety and tolerability of NTX-301 and to identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D). It will initiate with a dose escalation using a 3+3 design.

Combination Dose and Disease Expansion (Phase 1b-2a, n~60): The study will be expanded in specific subsets of patients with solid tumours and with combination therapy as follows:

  • Arm 1 (Phase 1b, n~20): Dose Escalation, NTX-301 platinum-based doublet therapy
  • Arm 2 (Phase 2a, n~40): Dose Expansion, NTX-301 platinum-based doublet therapy

Patients with advanced ovarian \& bladder cancer considered to be incurable by the investigator and for which available anti-cancer therapy has been exhausted will be enrolled for this component. Patients will be given NTX-301 at the MTD determined in Phase 1a. This will be combined with a platinum-based agent that will be administered by IV infusion.

Optional Cohort -High-Grade Glioma Combination Dose \& Disease Expansion (Phase 1b-2a, n~40)

  • Arm 3 (Phase 1b, n~20): Dose Escalation, NTX-301 combination therapy with TMZ
  • Arm 4 (Phase 2a, n~20): Dose Expansion, NTX-301 combination therapy with TMZ

Patients with IDH1 mutated high-grade glioma that have commenced initial chemoradiotherapy with temozolomide and are yet to commence Temozolomide maintenance therapy will be enrolled for this component. Patients will be given NTX-301 at the MTD determined in Phase 1a. This will be combined with TMZ that will be administered orally.

Being tested
NTX-301, Platinum-based Chemotherapy, Temozolomide
Keywords
Hypomethylating Agent, Nucleoside Analog, DNA Demethylation, Solid Tumors, Ovarian Neoplasms, Urinary Bladder Neoplasms, Platinum-resistant, Carboplatin, Cisplatin, Glioma, IDH1, Temozolomide
Medical subject headings
Glioma, Ovarian Neoplasms, Urinary Bladder Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NTX-301Drug

    Oral hypomethylating agent

  • Platinum-based ChemotherapyDrug

    Also called Cisplatin, Carboplatin

    Standard of care for ovarian and bladder cancer

  • TemozolomideDrug

    Standard of care for high-grade glioma

Study groups in NCT04851834
Study groupRoleWhat they receive
NTX-301 Monotherapy Dose EscalationExperimentalNTX-301 monotherapy dose escalation in patients with advanced solid tumours
Receives: Drug: NTX-301
NTX-301 platinum-based doublet therapy Dose EscalationExperimentalNTX-301 combined with platinum-based chemotherapy in platinum-resistant advanced ovarian \& bladder cancer
Receives: Drug: NTX-301; Drug: Platinum-based Chemotherapy
NTX-301 platinum-based doublet therapy Dose ExpansionExperimentalNTX-301 combined with platinum-based chemotherapy in platinum-resistant advanced ovarian \& bladder cancer
Receives: Drug: NTX-301; Drug: Platinum-based Chemotherapy
NTX-301 Temozolomide doublet therapy Dose EscalationExperimentalNTX-301 combined with Temozolomide (TMZ) as adjuvant (maintenance) treatment in IDH1 mutated high-grade glioma
Receives: Drug: NTX-301; Drug: Temozolomide
NTX-301 Temozolomide doublet therapy Dose ExpansionExperimentalNTX-301 combined with Temozolomide (TMZ) as adjuvant (maintenance) treatment in IDH1 mutated high-grade glioma
Receives: Drug: NTX-301; Drug: Temozolomide

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: 15 Months

  2. Safety & Tolerability: Dose-limiting Toxicities (DLT)

    Measured: 15 Months

Secondary outcomes (6)

  1. Incidence of DLTs according to the MTD/RP2D evaluation process

    Measured: 12 Months

  2. Pharmacokinetics (PK): Maximum observed concentration (Cmax)

    Measured: 12 Months

  3. Pharmacokinetics (PK): Time to Cmax (Tmax)

    Measured: 12 Months

  4. Pharmacokinetics (PK): Trough concentrations

    Measured: 12 Months

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

    Measured: 12 Months

  6. Pharmacokinetics (PK): Apparent terminal elimination half-life (t1/2)

    Measured: 12 Months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Apr 2021
  2. Study start25 Aug 2021
  3. Primary completion8 Nov 2022
  4. Study completion8 Nov 2022

Why it stopped: Study was terminated by IP Holder (collaborator), PinotBio Inc.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
Dose escalation to determine MTD/RP2D, then dose expansion
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04851834
Sponsor's protocol ID
XNTR-20-02
Status last verified
Dec 2022
First submitted
8 Apr 2021
Last updated
20 Dec 2022
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing NTX-301, Platinum-based Chemotherapy and Temozolomide in people with Advanced Solid Tumor and Platinum-Resistant Ovarian Cancer, run by Xennials Therapeutics Australia Pty Ltd at 2 sites in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 28 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 20 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Study was terminated by IP Holder (collaborator), PinotBio Inc.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety & Tolerability: Incidence, type, and severity of Adverse Events (AE) (time frame: 15 Months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04851834.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Dec 2022.

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