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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04851834




Registration number
NCT04851834
Ethics application status
Date submitted
8/04/2021
Date registered
20/04/2021
Date last updated
20/12/2022

Titles & IDs
Public title
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
Scientific 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)
Secondary ID [1] 0 0
XNTR-20-02
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Solid Tumor 0 0
Platinum-Resistant Ovarian Cancer 0 0
Platinum-Resistant Urothelial Carcinoma 0 0
High-grade Glioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - NTX-301
Treatment: Drugs - Platinum-based Chemotherapy
Treatment: Drugs - Temozolomide

Experimental: NTX-301 Monotherapy Dose Escalation - NTX-301 monotherapy dose escalation in patients with advanced solid tumours

Experimental: NTX-301 platinum-based doublet therapy Dose Escalation - NTX-301 combined with platinum-based chemotherapy in platinum-resistant advanced ovarian & bladder cancer

Experimental: NTX-301 platinum-based doublet therapy Dose Expansion - NTX-301 combined with platinum-based chemotherapy in platinum-resistant advanced ovarian & bladder cancer

Experimental: NTX-301 Temozolomide doublet therapy Dose Escalation - NTX-301 combined with Temozolomide (TMZ) as adjuvant (maintenance) treatment in IDH1 mutated high-grade glioma

Experimental: NTX-301 Temozolomide doublet therapy Dose Expansion - NTX-301 combined with Temozolomide (TMZ) as adjuvant (maintenance) treatment in IDH1 mutated high-grade glioma


Treatment: Drugs: NTX-301
Oral hypomethylating agent

Treatment: Drugs: Platinum-based Chemotherapy
Standard of care for ovarian and bladder cancer

Treatment: Drugs: Temozolomide
Standard of care for high-grade glioma
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Safety & Tolerability: Incidence, type, and severity of Adverse Events (AE)
Timepoint [1] 0 0
15 Months
Primary outcome [2] 0 0
Safety & Tolerability: Dose-limiting Toxicities (DLT)
Timepoint [2] 0 0
15 Months
Secondary outcome [1] 0 0
Incidence of DLTs according to the MTD/RP2D evaluation process
Timepoint [1] 0 0
12 Months
Secondary outcome [2] 0 0
Pharmacokinetics (PK): Maximum observed concentration (Cmax)
Timepoint [2] 0 0
12 Months
Secondary outcome [3] 0 0
Pharmacokinetics (PK): Time to Cmax (Tmax)
Timepoint [3] 0 0
12 Months
Secondary outcome [4] 0 0
Pharmacokinetics (PK): Trough concentrations
Timepoint [4] 0 0
12 Months
Secondary outcome [5] 0 0
Pharmacokinetics (PK): Area under the concentration-time curve (AUC0-t)
Timepoint [5] 0 0
12 Months
Secondary outcome [6] 0 0
Pharmacokinetics (PK): Apparent terminal elimination half-life (t1/2)
Timepoint [6] 0 0
12 Months

Eligibility
Key inclusion criteria
1. Ability to understand and be willing to sign an informed consent form.

2. Male or female, = 18 years old at the time of screening.

3. Diagnosis of histologically or cytologically confirmed:

1. 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

2. 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

3. 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.

4. Eastern Cooperative Oncology Group performance status of 0 to 1

5. Able to take oral medications and willing to record daily adherence to the study drug.

6. Cardiac

1. 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)

2. LVEF >45% based on ECHO Scan within 60 Days of screening.

7. Evidence of adequate hepatic function at screening, as defined by the following:

1. AST and ALT =2.5 × upper limit of normal (ULN) (=5 × ULN if liver metastases are
present); and

2. Total bilirubin =1.5 × ULN (< 2.0 x ULN for subjects with liver metastases or
documented Gilbert's syndrome).

8. Adequate haematology laboratory assessment at screening, as defined by:

1. Absolute neutrophil count =1.00 x109/L;

2. Haemoglobin =90 g/L; and

3. Platelet count =100 x109/L.

9. 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.

10. Adequate coagulation laboratory assessments (i.e., within normal reference range
values) at screening, in the opinion of the Investigator.

11. Female subjects must:

1. 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

2. 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.

12. 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

13. 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.

14. Willing and able to comply with all scheduled visits, treatment plans, laboratory
tests, and other study procedures.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Investigational agents, including hypomethylating agents, in the past 5 half-lives

2. Patients with symptomatic brain metastases.

3. Evidence of abnormal cardiac function as defined by any of the following:

1. Myocardial infarction within 6 months of Cycle 1, Day 1

2. Symptomatic congestive heart failure (New York Heart Association > class II)

3. Unstable angina

4. 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.

4. Unable to swallow oral medications.

5. Gastrointestinal (GI) Gastrointestinal conditions that, in the opinion of the
Investigator, could affect the absorption of NTX-301

6. 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).

7. 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):

1. Certain Medications defined within the study protocol

2. Foods: Grapefruit or Seville orange (or grapefruit- or Seville orange-containing
products, including juices).

8. 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)

9. Clinically significant active infection within 2 weeks of the first dose of NTX-301
(Cycle 1, Day 1).

10. 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.

11. History of other malignancy within the past 2 years, with the following exceptions:

1. 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.

2. Adequately treated non-melanoma skin cancer or lentigo malignancy without
evidence of disease.

3. Adequately treated cervical carcinoma in situ without evidence of disease.

4. Adequately treated breast ductal carcinoma in situ without evidence of disease.

5. Prostatic intraepithelial neoplasia without evidence of prostate cancer.

6. Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in
situ.

12. Major surgery within 28 Days of Cycle 1, Day1, with the following exceptions:

1. Major surgical procedures =28 Days of beginning study drug, or

2. Minor surgical procedures =7 Days.

3. No waiting required following port-a-cath placement or for venous access.

4. 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.

13. Received cancer-directed therapy within the following timeframes:

1. 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.

2. 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.

3. 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.

14. 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):

i. Subjects with chronic Grade 2 toxicities may be eligible per discretion of the
Investigator and Sponsor (e.g., Grade 2 chemotherapy induced neuropathy).

ii. 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

15. For women of childbearing potential, a positive pregnancy test at screening, or on Day
1, prior to dose administration.

16. Pregnant or breast-feeding (or planning to breastfeed while on study through 15 Days
after the last dose of study drug.

17. Hypersensitivity or other clinically significant reaction to the study drug or its
inactive ingredients.

18. 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.

19. 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

20. COVID-19 vaccinations: Administration of an approved COVID-19 vaccine less than14 Days
prior to dosing.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
25/08/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
8/11/2022
Sample size
Target
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
St. Vincent's Hospital - The Kinghorn Cancer Center - Darlinghurst
Recruitment hospital [2] 0 0
St. George Private Hospital - Kogarah
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
2217 - Kogarah

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Xennials Therapeutics Australia Pty Ltd
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Pinotbio, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04851834
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Joyce L. Steinberg, MD
Address 0 0
Xennials Therapeutics Inc
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04851834