Overview

Study of CX-5461 in Patients With Solid Tumours and BRCA1/2, PALB2 or Homologous Recombination Deficiency (HRD) Mutation

Status:
Recruiting
Trial end date:
2025-09-30
Target enrollment:
0
Participant gender:
All
Summary
This is an open-label, multi-center, phase 1b study designed to determine a tolerable dose of CX-5461 administered by IV infusion on Day 1 and Day 8 of a 28-day cycle in patients with selected solid tumours and associated mutations for future Phase II trials. The safety and tolerability of CX-5461, preliminary evidence of antitumor effect and the effect of CX-5461 on the Health-Related Quality of Life (HRQoL) will also be evaluated. The study will also evaluate the predictive value of mutational signatures and explore the significance of dynamic changes in ctDNA levels and plasma DNA methylome profiling in this study's exploratory cohort.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Senhwa Biosciences, Inc.
Criteria
Inclusion Criteria:

Main study cohort:

1. Histologically or cytologically confirmed malignancy of the pancreas, prostate,
breast, or ovary.

2. Documented evidence of pathogenic or likely pathogenic germline mutation in BRCA2
and/or PALB2 as indicated in a Clinical Laboratory Improvement Amendments
(CLIA)-certified laboratory report. The report must be submitted to and approved by
study sponsor prior to registration. Patients with somatic BRCA2 and/or PALB2 mutation
are allowed provided that these patients also have corresponding germline pathogenic
or likely pathogenic BRCA2 and/or PALB2 mutation.

3. Patients must have measurable disease as per RECIST 1.1.

Exploratory cohort:

1. Histologically confirmed ovarian, fallopian tube or primary peritoneal cancer, with a
high grade serous or high grade endometrioid histology subtype.

2. Documented evidence of pathogenic or likely pathogenic germline mutation or a
clinically actionable somatic mutation in BRCA1 and/or other HRD-associated mutation,
as indicated in a CLIA-certified laboratory report. The report must be submitted to
and approved by study sponsor prior to registration.

3. Patients must have measurable disease as per RECIST 1.1.

4. Meet one of the following criteria:

1. Platinum Sensitive with no evidence of disease progression within 6 months of the
last dose of platinum-based chemotherapy (n=10 patients); OR

2. Platinum Resistant with disease progression within 6 months of the last dose of a
platinum-based chemotherapy.

All participants:

1. Age ≥ 18 years.

2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 within 14 days of
registration.

3. Radiographically documented disease progression within 28 days of registration and
evaluable as per RECIST v1.1.

4. Patients must have adequate bone marrow, renal and hepatic function per local
laboratory reference ranges as follows within 14 days of registration:

1. Absolute Neutrophil Count ≥ 1.5 x 10^9/L

2. Platelets ≥ 100 x 10^9/L

3. Hemoglobin ≥ 9 g/dL (blood transfusion ≤ 7 days of screening not permitted).

4. Calculated creatinine clearance > 51mL/min (Cockcroft-Gault formula)

5. AST/ALT ≤ 2.5× the upper limit of normal (ULN). Subjects with liver metastasis
may have AST, ALP, and ALT ≤ 5.0 X ULN.

6. Bilirubin ≤ 1.5×ULN. This will not apply to patients with confirmed Gilbert's
syndrome (persistent or recurrent hyperbilirubinemia that is predominantly
unconjugated in the absence of haemolysis or hepatic pathology), who will be
allowed only at the discretion of the Study Investigator.

7. INR/PT and aPTT ≤1.5 X ULN unless patient is receiving anticoagulant therapy as
long as PT or PTT is within therapeutic range of intended use of anticoagulants.

8. Albumin ≥3.0 g/dL

5. Patients are willing to undergo tumour biopsy pre-treatment and at time of progression
on treatment. If a biopsy at the time of progression on prior therapy is available and
can be submitted to the Central Lab for this study, this procedure does not need to be
repeated. Patients who consent but have tumour that is not amenable to safe biopsy
will be allowed to enter the trial and continue therapy as per protocol if this has
been addressed and permission is granted from the sponsor prior to registration.

6. Life expectancy of greater than 3 months from the date of registration.

7. Able to provide written informed consent.

8. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

9. Female patients of childbearing potential must have a negative serum pregnancy test
within 14 days prior to registration. (Note: a negative urine/serum pregnancy test is
required on Cycle 1, Day 1 prior to treatment unless the screening pregnancy test was
done within 48hrs of registration).

10. Female patients of childbearing potential and male patients who are sexually active
must agree to practice true abstinence or at least two effective methods of
contraception (ie: condoms with spermicide, hormonal methods such as oral
contraceptive pills, vaginal ring, injectables, implants and intrauterine devices
(IUDs), non-hormonal IUDs, such as ParaGard, bilateral tubal ligation, vasectomy,
complete abstinence) within 14 days prior to registration, and agree to continue using
such precautions while on treatment with CX-5461 (including dose interruptions) and
for 6 months following the last dose of CX-5461.

11. There is no minimum or maximum number of lines of prior therapy and prior PARP
inhibitor therapy is allowed.

Exclusion Criteria:

1. For pancreatic cancer; non-adenocarcinoma histology is excluded from this study.

2. Patients with malignant bowel obstruction.

3. Patients with a history of spinal cord compression.

4. Untreated, unstable brain or meningeal metastases or tumor. Patients with radiological
evidence of stable brain metastases are eligible provided that they are asymptomatic
and either do not require corticosteroids or have been treated with corticosteroids,
with clinical and radiological evidence of stabilization at least 10 days after
discontinuation of steroids.

5. Unresolved toxicity > CTCAE grade 1 from previous anti-cancer therapy (including
radiotherapy) except hematological toxicity and alopecia.

6. Any evidence of severe or uncontrolled diseases such as but not limited to active
infection, unstable or uncompensated respiratory, cardiac, neurological, hepatic,
renal disease or psychiatric illness/social situations, which in the opinion of the
investigator, would limit compliance with study requirements.

7. Treatment with an investigational (non-registered - other than PARP inhibitor) agent
within 30 days and treatment with PARP inhibitor within 14 days prior to the first
dose of study medication.

8. Immuno-compromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV), patients with known active hepatitis (i.e.,
hepatitis B or C). Note: Patients with a prior history of treated HBV infection who
are antigen-negative or patients with a prior history of treated HCV infection who are
HCV RNA-undetectable may be enrolled. Patients who are known to be serologically
positive for human immunodeficiency virus (HIV) can enroll if their CD4+ T-cell (CD4+)
counts ≥ 350 cells/uL.

9. Patients who have had recent (within 14 days of registration, or until any wound has
completely healed) major thoracic or abdominal surgery prior to study start, or a
surgical incision that is not fully healed.

10. No concurrent systemic anti-cancer therapy, biological therapy or other novel agent is
to be permitted. Palliative radiotherapy may be allowed. If radiotherapy is required
due to disease progression, patient will be considered off study. If radiotherapy is
be used to treat non-target lesions and patients may benefit from continuing on study
treatment, CX-5461 may re-commence 14 days after completion of radiotherapy. Any
continuation on study treatment must be discussed with and approved by study sponsor.

11. Patients may be potentially eligible where the current tissue diagnosis is confirmed
histologically from biopsy of a target lesion, and the patient has had no evidence of
active second malignancy which requires treatment or would confound interpretation of
safety, tolerability and efficacy of CX-5461. These cases must be discussed with the
medical monitor prior to confirm eligibility.

12. Presence of known photosensitivity disorders (xeroderma pigmentosa, porphyria etc.).
Strict adherence to protocol-defined sun-protection measures is essential for the
duration of study. Patients who do not agree to follow these measures are not
eligible. Patients who do not agree to use sunglasses and sun blocker (with SPF50 to
UVB and a high degree of protection against UVA) if exposed to sunlight during the
course of the study and for 3 months after the last dose are not eligible. Patients
who plan to use sunbeds or tanning booths during the course of the study and within 3
months after the last dose are not eligible.

13. Female patients who are pregnant or nursing.

14. Patients who have a positive COVID-19 test within 14 days of starting study treatment.
Patients that test positive can re-test after the 14-day exclusion and may be eligible
if the re-test is negative.

15. Ophthalmological: active ocular surface disease at baseline (based on an
ophthalmological evaluation).

16. History of cicatricial conjunctivitis (as evaluated by an ophthalmologist).

17. Has had radiotherapy with a limited field for palliation within 1 week of the first
dose of study drug, with the exception of patients receiving radiation to more than
30% of the bone marrow or with a wide field of radiation, which must be completed at
least 4 weeks prior to the first dose of study drug.

18. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a
QTc interval >450 ms).

19. A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family
history of long QT syndrome).

20. The use of concomitant medications that prolong the QT/QTc interval.

21. Patients with the use of strong CYP3A4 inhibitor or inducer.

22. Other malignancies within 5 years except for noninvasive malignancies such as cervical
carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal carcinoma in situ
of the breast that has been surgically cured. Cancer patients with incidental
histologic findings of prostate cancer (tumour/node/metastasis stage T1a or T1b or
prostate-specific antigen <10 ng/mL) who have not received hormonal treatment may be
included, pending a discussion with the Study Sponsor.