Phase 1/2 Study of SX-682 in Combination with Apalutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Switzerland, United Kingdom (ICTRP)

ICTRP Trial ID
NCT07002320 (ICTRP)

Official title (approved by ethics committee)
ASpiRE: uno studio clinico prova del meccanismo (proof-of-mechanism) e prova di concetto (proof-of-concept) che valuta la sicurezza, la tollerabilità, l'attività biologica e antitumorale di Apalutamide con il doppio blocco di CXCR1 e CXCR2 da parte di SX-682 per uomini affetti da carcinoma prostatico metastatico resi-stente alla castrazione (mCRPC) (BASEC)

Academic title
ASpiRE: A Proof-of-mechanism and Proof-of-concept Clinical Trial Evaluating the Safety, Tolerability, Biological and Anti-tumour Activity of Apalutamide With Dual CXCR1 and CXCR2 Blockade by SX-682 for Men Suffering From Metastatic Castration-resistant Prostate Cancer (mCRPC) (ICTRP)

Public title
Investigating SX-682 in Combination With Apalutamide in Metastatic Castration-resistant Prostate Cancer (ICTRP)

Disease under investigation
Metastatic Castrate-Resistant Prostate Cancer (mCRPC) (ICTRP)

Intervention under investigation
Drug: SX-682Drug: Apalutamide (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Non-Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion criteria
Inclusion Criteria:

1. Written informed consent and be capable of cooperating with treatment.

2. Age = 18 years.

3. Histologically or biochemically confirmed adenocarcinoma of the prostate and with
tumour tissue accessible for research analysis for this trial. Patients who have no
histological diagnosis must be willing to undergo a biopsy to prove prostate
adenocarcinoma.

4. Patients recruited to phase 1 dose escalation cohorts must have biopsiable disease
and consent to mandatory pre- and post-treatment biopsies (baseline and on Cycle 2
Day 1).

5. Metastatic castration-resistant prostate cancer.

6. All patients must have documented resistance to 1 prior next generation antiandrogen
therapy (NAAT) defined as:

For phase 1 and phase 2 Cohorts:

Patients who have progressed after either enzalutamide, Apalutamide or darolutamide
(having received a minimum of 12-weeks of enzalutamide, Apalutamide or darolutamide)
will enter phase 1 or phase 2 cohorts directly. Patients that have previously
received abiraterone but not an AR antagonist should receive a lead-in with
Apalutamide on trial and receive the combination on progression through the lead-in.

7. Documented prostate cancer progression as assessed by the investigator with RECIST
v1.1 and PCWG3 criteria (Section 3.5) with at least two of the following criteria:

1. Progression of soft tissue/visceral disease by RECIST v1.1 and/or,

2. Progression of bone disease by PCWG3 bone scan criteria and/or,

3. Progression of PSA by PCWG3 PSA criteria.

8. PSA = 10ng/ml.

9. Received prior castration by orchiectomy and/or ongoing luteinizing hormone
releasing hormone agonist treatment.

10. Ongoing androgen deprivation with serum testosterone < 50 ng/dL (< 1.7 nM).

11. Eastern Cooperative Oncology Group (ECOG) Performance Status of =2.

12. Documented willingness to use an effective means of contraception while
participating in the study and for 6 months post last treatment dose.

13. Able to swallow the study drug.

14. All efforts should be made to discontinue steroid usage but up-to 5mg BD
prednisolone (or equivalent) will be allowed.

15. Haematological and biochemical indices within the ranges shown below. These
measurements must be performed within one week (Day -7 to Day 1) before the patient
goes on trial.

Haemoglobin (Hb) = 9.0 g/dL Absolute neutrophil count = 1.5 x 109/L Platelet count = 100
x 109/L WBC = 3.0 x 109/L Calculated creatinine clearance = 50 mL/min (uncorrected value)
Serum bilirubin = 1.5 x upper limit of normal (ULN) unless documented Gilbert's disease.,
in which case = 3 x ULN is permissible Alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) = 2.5 x (ULN) unless raised due to known metastatic liver disease
in which case = 5 x ULN is permissible

Exclusion Criteria:

1. Surgery, chemotherapy, or other anti-cancer therapy within 4 weeks prior to trial
entry/randomisation into the study (with the exception of abiraterone, enzalutamide,
Apalutamide or darolutamide). Any other therapy for prostate cancer, other than
gonadotropin releasing hormone analogue therapy, such as progesterone,
medroxyprogesterone, progestins or 5-alpha reductase inhibitors, must be
discontinued at least 2 weeks before the first dose of the study drug.

2. Participation in another interventional clinical trial of an IMP within 4 weeks
prior to trial entry. Participation in trials of licensed medications is allowed
provided the medication is not a prohibited concomitant medication.

3. Prior limited field radiotherapy within 2 weeks and wide field radiotherapy within 4
weeks prior to trial entry.

4. Clinical and/or biochemical evidence of hyperaldosteronism or hypopituitarism.

5. History of seizures or other predisposing factors including, but not limited to,
underlying brain injury, stroke, primary brain tumours, brain metastases and
leptomeningeal disease, or alcoholism.

6. Malabsorption syndrome or other condition that would interfere with enteral
absorption.

7. Any of the following cardiac criteria:

- QTcF interval > 470 msec.

- Clinically important abnormalities including rhythm, conduction, or
electrocardiogram (ECG) changes (left bundle branch block, third degree heart
block).

- Factors predisposing to QT prolongation including heart failure, hypokalaemia,
congenital long QT syndrome, family history of prolonged QT syndrome,
unexplained sudden death (under 40) and concomitant medications known to
prolong QT interval.

- Coronary artery bypass, angioplasty, vascular stent, myocardial infarction,
angina, congestive heart failure (NYHA = grade 2) i or transient ischaemic
attack) in the last 6 months (see appendix 4 for NYHA scale).

- Uncontrolled hypotension (systolic blood pressure < 90mmHg).

- Uncontrolled hypertension on optimal medical management.

8. Clinically significant history of liver disease (Child-Pugh B or C, viral or other
hepatitis, current alcohol abuse or cirrhosis).

9. Any other finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect interpretation
of the results or renders the patients at high risk from treatment complications,
e.g., patients with a hypersensitivity to the active substance or any of the
excipients.

10. Malignancy other than prostate cancer within 5 years of trial entry except for
adequately treated basal cell carcinoma.

11. Unresolved significant toxicity from prior therapy (except alopecia and grade 1
peripheral neuropathy).

12. Inability to comply with study and follow-up procedures.

13. Predominantly small cell or neuroendocrine differentiated (> 20% of cells) prostate
cancer.

14. Immunocompromised patients.

15. Active or uncontrolled autoimmune disease requiring corticosteroid therapy.

16. History of thromboembolic disease within 12 months of commencement of trial.

17. At high-risk because of non-malignant systemic disease including active infection
and any serious concurrent illness.

18. Any known intolerance to Apalutamide, SX-682, or to any constituents.

19. Symptoms of COVID-19 and/or documented COVID-19 infection.

20. Is taking any of the following prohibited medications:

- Aminophylline/theophylline

- Atypical antipsychotics (eg, clozapine, olanzapine, risperidone, ziprasidone)

- Buproprion

- Lithium

- Meperidine and pethidine

- Phenothiazine antipsychotics (eg, chlorpromazine, mesoridazine, thioridazine)

- Tricyclic and tetracyclic antidepressants (eg, amitriptyline, desipramine,
doxepin, imipramine, maprotiline, mirtazapine

- Warfarin or coumarin-like anticoagulants

21. History of previous non-infectious pneumonitis requiring steroid treatment, or
active non-infectious pneumonitis.

22. History of previous severe drug induced severe cutaneous reaction including but not
limited to Steven-Johnson's syndrome/toxic epider (ICTRP)

not available

Primary and secondary end points
Biologically active and tolerable dose range;Anti-tumour activity of SX-682 when administered with Apalutamide (ICTRP)

Safety and tolerability profile as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0;Steady state pharmacokinetic parameters (CSSmin and CSSMax);Number of patients with Prostate Specific Antigen (PSA) decline greater than 50%;Soft tissue objective response (CR or PR) by RECIST v1.1;Changes in circulating tumour DNA (ctDNA) tumour fractions (TF).;Progression free survival;Overall survival;Relative changes in circulating neutrophils;Impact on quality of life using Brief Pain Inventory (BPI) Questionnaire;Impact of treatment toxicity using Functional Assessment of Chronic Illness Therapy (FACIT)-GP5 Questionnaire;Relative changes in intra-tumour myeloid derived suppressor cells (MDSCs) (ICTRP)

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
Prostate Cancer UK;Janssen Pharmaceutica N.V., Belgium;Oncology Institute of Southern Switzerland;Syntrix Biosystems, Inc.;Royal Marsden NHS Foundation Trust;Cambridge University Hospitals NHS Foundation Trust;Belfast Health and Social Care Trust;Institute of Oncology Research (IOR) (ICTRP)

Additional contacts
Professor Johann de Bono, MB ChB, FRCP, MSc, PhD, FMedScAasia Hussain, PhD, ASPIRE@icr.ac.uk, 02034376301, Institute of Cancer Research, United Kingdom (ICTRP)

Secondary trial IDs
1008729, CCR6041 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/study/NCT07002320 (ICTRP)