A Phase 1/2a, Open-Label, Safety, Pharmacokinetic, and Preliminary

Recruiting

18 years and older

All

Phase 1

10 participants needed

5 Locations

Brief description of study

The study will evaluate the safety profile of escalating doses of continuous daily oral ATRN-119 and to determine the maximum tolerated dose (MTD) and recommended dose. ATRN-119 is a drug that has been developed to treat cancers by taking advantage of genetic mutations found only in the tumor and not in normal tissue.

Detailed description of study

ATRN-119 will be supplied as 50 mg, 100 mg and/or 200 mg HPMC (hydroxypropyl methylcellulose) capsules packed in sealed plastic bottles (n=30 each) dispensed by the site pharmacist in combinations to provide the appropriate dose.

ATRN-119 once daily schedule includes 50 mg PO QDay, 100 mg PO QDay, 200 mg PO QDay, 350 mg PO QDay, 550 mg PO QDay, 800 mg PO QDay, 1100 mg PO QDay, 1300 mg PO QDay, and 1500 mg PO QDay dose levels. ATRN-119 BID schedule

potentially includes 400 mg PO BID, 550 mg PO BID, 650 mg PO BID, and 750 mg PO BID. The BID ATRN-119 will be taken once in the morning and once in the evening, approximately 12 hours apart.

Except for PK evaluation days (C1D1, C1D2, and C2D1), ATRN-119 will be taken with water at least 1 hour before a meal, or at least 1 hour after a meal. Patients will be instructed to wait at least one hour after taking ATRN-119 before eating again.

A food effect PK study will be initiated for all patients enrolling in dose escalation under Version 6 of this protocol. Patients will be instructed to fast overnight (for at least 10 hours) before their clinic visit on Cycle 1 Day 1 for fasted state administration of ATRN-119. Patients will be instructed to fast overnight (for at least 10 hours) before their clinic visit on Cycle 1 Day 2 for fed state administration of ATRN-119.

To facilitate the food-effect study in dose escalation, all patients will be administered a single dose of ATRN-119 on Cycle 1 Day 1 and 2. Patients assigned to twice daily administration will start BID administration on Cycle 1 Day 3.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

Conditions: Advanced Solid Tumors including ovarian, endometrial and cervical cancer
Age: 18 Years
Gender: All

Main Inclusion Criteria

For a patient to be eligible for this study, s/he must meet ALL of the following criteria:

1. 12 years of age or older.

2. Patients may be enrolled with advanced solid tumor that has at least one of the following DDR mutations documented in their past medical record or confirmed during the screening period. Gene mutations in tumor tissue must be determined by a CLIA-certified NGS method (such as, e.g., FoundationOne CDx NGS assay). Liquid biopsy in lieu of tumor tissue may be used to confirm DDR mutations during screening. DDR genomic variants will be reviewed during eligibility and documented in the CRF. Eligible patients must have documented presence of at least one of the following:

a. Any mutation in ARID1A, including but not limited to missense mutations, nonsense mutations, truncating mutations, frameshift mutations, splicing mutations, and deep deletions.

b. Any missense mutation in KRAS at Gly12 and/or Gly 13.

c. Probable loss of function mutations (including nonsense mutations, truncating mutations, frameshift mutations, splicing mutations, and deep deletions) in ATM, ATR, ATRX, BRCA1, BRCA2, BRIP1, CCNK, CDK12, CDKN2A, CHEK1, EZH2, FANCA, FANCC, FANCM, HP1BP3, HUS1, MDC1, MLH1, MRE11A, MSH2, MSH6, MTAP, NBN, NEDD4, PALB2, PARP1, PMS2, POLD1, POLE, PMS2, PPP2RA, RAD50, RAD51, RAD51B, RAD51C, RB1, RNASEH2B, RPA1, SETD2, SIAH1, SMARCA2, SMARCA4, TOPBP1, TPT1, UBR5, USP9X, WRN, XRCC1, XRCC2 or XRCC5.

d. Amplification (>4 genomic copies in total) of MYC, CCNE1, or CCNE2.

e. Patients with advanced Merkel cell carcinoma (MCC) are eligible for both dose escalation and dose expansion regardless of known mutation status.

3. Measurable disease defined by RECIST 1.1 or, for mCRPC subjects, by PCWG3 criteria.

4. Patient must have failed (demonstrated progression or intolerable safety events) at least one prior approved standard of care (SOC) therapy prior to entry into the study.

5. Life expectancy ≥ 3 months.

6. Patient must be capable of oral administration of study medication.

7. Signed written informed consent.

8. If receiving corticosteroids, patient must be on a stable or decreasing dose for at least 7 days prior to Day 1.

9. Adequate bone marrow, renal, and liver function as manifested by any of the following:

• Complete blood cell count (CBC): ANC ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and hemoglobin ≥ 9.0 g/dL.

• Coagulation profile with prothrombin time (PT) and international normalized ratio (INR), each ≤ 1.5 x upper limit of normal (ULN). Patients with stable prophylactic anticoagulant therapy and PT and/or INR > 1.5 x ULN, but within the intended therapeutic range, may be approved after discussion with the medical monitor.

• Creatinine clearance ≥ 50 mL/min calculated by Cockcroft-Gault formula.

• Serum bilirubin < 1.5 x ULN (< 3 x ULN for liver metastases) or if Gilbert syndrome then > 1.5 x ULN with normal direct bilirubin, aspartate transaminase (AST) and alanine transaminase (ALT) <3 x ULN (< 5 x ULN for liver metastases).

10. Corrected serum total calcium < 11.5 mg/dL.

11. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 or Karnofsky Performance Status (KPS) ≥ 70% for ≥ 16 years old and Lansky Play- Performance Scale ≥ 70% for < 16 years old.

12. If female, is not pregnant or breastfeeding based on the following:

a. a negative serum pregnancy test (ß-hCG) at Screening and negative urine or serum pregnancy test at Baseline; or

b. is of nonchildbearing potential defined as clinically infertile as the result of surgical sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy); or

c. is confirmed postmenopausal status (defined as either having amenorrhea for ≥ 12 consecutive months without another cause and documented serum follicle- stimulating hormone [FSH] level > 40 mIU/mL or another documented medical condition (e.g., was born without a uterus)), or agree to the use of highly effective contraceptive methods at screening until 45 days or 5 half-lives (whichever is longer) after the last day of study drug.

NOTE: The following are considered highly effective contraceptive methods: hormonal oral contraceptives, injectables, and patches; intrauterine devices; double-barrier methods (synthetic condom, diaphragm, or cervical cap used with spermicidal foam, cream, or gel); and male partner sterilization.

13. If male (with or without vasectomy), agree to the use of highly effective contraceptive methods (as listed in Criterion #12 above) at screening until 45 days or 5 half-lives (whichever is longer) after the last day of study drug.

Main Exclusion Criteria

Patients must NOT meet any of the following Exclusion criteria to be eligible for enrollment:

1. Known loss of function mutation in CCNC or CDK8.

2. Cytotoxic chemotherapy, immunotherapy, radiotherapy or other targeted therapies within 4 weeks (6 weeks in cases of mitomycin C, nitrosourea, lomustine) or at least 5 half-lives (whichever is shorter, but no less than 2 weeks) before the study drug administration. All treatment-related AEs (excluding alopecia) must have either returned to baseline or stabilized. Patients with prostate cancer may remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Patients with prior history of hormone positive breast cancer or prostate cancer may remain on adjuvant endocrine therapy, as long as it is not the disease under study.

3. Have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer, ductal carcinoma in situ, incidentally discovered asymptomatic thyroid cancer, and a previous diagnosis of malignancy that has shown no evidence of disease progression for 5 years or longer.

4. Surgical procedure performed within 7 days prior to first scheduled dose of ATRN-119.

5. Concomitant treatment with strong inhibitors or strong inducers of the CYP enzymes.

6. Known human immunodeficiency virus infection (HIV).

7. Patients with active viral or bacterial infections and/or receiving systemic antibiotics and anti-viral medications.

8. Current or past diagnosis of leukemia within the past 5 years.

9. Prior radiotherapy at the target lesion unless there is evidence of disease progression.

10. Known central nervous system (CNS) metastases or clinical evidence of CNS involvement that is not stable for previous 1 month by radiology documentation (magnetic resonance imaging [MRI] brain).

11. History of non-malignant gastrointestinal (GI) bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months that, in the opinion of the Investigator, may place the patient at risk of adverse effects on an anti- angiogenesis product.

12. Patient has uncontrolled hypertension at time of enrollment.

13. Complete left bundle branch block (LBBB), bifascicular block (right bundle branch block [RBBB] with either left anterior hemiblock or left posterior hemiblock).

14. Any clinically significant ST segment and/or T-wave abnormalities.

15. Presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation are allowed in the study provided they do not meet another exclusion criteria.

16. Myocardial infarction or unstable angina pectoris within 6 months prior to starting study medication.

17. Congestive heart failure (New York Heart Association class III-IV).

18. History of other significant cardiovascular disease or vascular disease within the last 6 months (e.g., such as hypertensive crisis, hypertensive encephalopathy, stroke or transient ischemic attack [TIA], or significant peripheral vascular disease).

19. QTcF > 470 msec for male and female patients, based on the average of three ECG measurements at the screening visit.

20. Echocardiogram or multiple gated acquisition scanning (MUGA) (within 2 months) with left ventricular ejection fraction (LVEF) <50%.

21. Recent history of clinically significant glomerulonephritis, biopsy proven tubulointerstitialnephritis, crystal nephropathy, or other renal insufficiencies.

22. Treatment with an investigational agent within the longest time frame of either 5 half-lives or 30 days of initiating study drug.

23. Medical illness that, in the opinion of the Investigator, may impact the safety of the patient or objectives of the study. Known recreational substance use or psychiatric illness that, in the opinion of the Investigator, may affect compliance with scheduled visits.

24. Known hypersensitivity to ATRN-119 or components of the formulation.

25. Recent history of clinically significant renal impairment.

26. History of clinically significant liver disease, liver impairment or any other liver anomality which may affect drug metabolism.

Updated on 02 Nov 2024. Study ID: 849959

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