Chk2 Inhibitor for Recurrent EpitheliAl periToneal, fallopIan or oVarian cancEr (CREATIVE Phase IA Trial)

NCT04678102 | Unknown Phase 1 DMC

• 1 other identifier: PHI-101-002
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to assess the safety and tolerability of PHI-101 in patients with platinum-resistance/refractory ovarian, fallopian tubal, and primary peritoneal cancer. This study also evaluates the pharmacokinetics of PHI-101 and efficacy of PHI-101 during treating platinum-resistance/refractory ovarian, fallopian tubal, and primary peritoneal cancer. PHI-101 is a CHK2 inhibitor that is a checkpoint kinase binding specifically to CHK2, rather than CHK1, and it inhibits the DDR system by inhibiting the ATM-CHK2 pathway, which is activated in response to DSBs. When a high-grade serous ovarian (HGSO) cancer cell line and various ovarian cancer cell lines (CAOV3, OVCAR3, SK-OV-03, and SW626) were treated with PHI-101 in a non-clinical study, the therapeutic effect of PHI-101 against ovarian cancer was demonstrated by a decrease in viability of ovarian cancer cells. In addition, a stronger growth inhibition effect was observed compared to that of treatment with olaparib or rucaparib alone, and a much stronger inhibition effect was observed when concomitantly used with paclitaxel, cisplatin, and topotecan. Based on the aforementioned results of the non-clinical studies, the potential of PHI-101 as a new treatment or concomitant cytotoxic chemotherapeutics for patients with ovarian cancer who are resistant to existing antineoplastic drugs was confirmed.

Conditions

Platinum-resistant Ovarian Cancer; Platinum-refractory Ovarian Carcinoma; Platinum-Resistant Fallopian Tube Carcinoma; Platinum-Resistant Primary Peritoneal Carcinoma

Keywords

PHI-101; Chk2 inhibitor; antineoplastic; Platinum-resistant Ovarian Cancer

Outcome Measures

Primary Outcomes (2)

• Proportion of patients with dose-limiting toxicity (DLT)

  The frequency and percentage of DLT that occurs during 1 cycle (28 days) after administration of the IP will be presented by the cohort.

  Subjects will be treated and observed for DLT through the end of the first cycle (Days 1-28)

• Maximum tolerated dose

  The dose of PHI-101 will be escalated until an MTD is determined, and if the MTD is not determined at the MPD, dose escalation will be ended at that dose

  Through the first cycle (Day1-28)

Secondary Outcomes (23)

• Dose interruption (temporary discontinuation) percent (%)

  Through the first cycle (Day1-28)

• Dose reduction percent (%)

  Through the first cycle (Day1-28)

• Dose termination (permanent discontinuation) percent (%)

  Through the first cycle (Day1-28)

• Cmax

  Cycle1Day1, Cycle1Day8, Cycle1Day15, Cycle2Day1, Cycle3Day1, Cycle6day1, and then, every 12 weeks until end of the study, up until 24 months (each cycle is 28 days)

• AUCt

  Cycle1Day1, Cycle1Day8, Cycle1Day15, Cycle2Day1, Cycle3Day1, Cycle6day1, and then, every 12 weeks until end of the study, up until 24 months (each cycle is 28 days)

Study Arms (6)

Cohort 1 (PHI-101 40mg/day)

EXPERIMENTAL

In the starting dose cohort 1 subject will be administered 40mg/day PHI-101 and will be assessed for DLT ('single subject cohort'), and until an ADR ≥ \[CTCAE version 5.0\] grade 2 occurs, higher doses will be explored in single subject cohorts in a stepwise fashion. If an ADR ≥ \[CTCAE version 5.0\] grade 2 occurs, the accelerated 3+3 design will be immediately switched to the standard 3+3 scheme.

Drug: PHI-101 administration

Cohort 2 (PHI-101 80mg/day)

EXPERIMENTAL

In cohort 2, the subject will be administered 80mg/day PHI-101.

Drug: PHI-101 administration

Cohort 3 (PHI-101 120mg/day)

EXPERIMENTAL

In cohort 3, the subject will be administered 120mg/day PHI-101.

Drug: PHI-101 administration

Cohort 4 (PHI-101 160mg/day)

EXPERIMENTAL

In cohort 4, the subject will be administered 160mg/day PHI-101.

Drug: PHI-101 administration

Cohort 5 (PHI-101 200mg/day)

EXPERIMENTAL

In cohort 5, the subject will be administered 200mg/day PHI-101.

Drug: PHI-101 administration

Cohort 6 (PHI-101 240mg/day)

EXPERIMENTAL

In cohort 6, the subject will be administered 240mg/day PHI-101.

Drug: PHI-101 administration

Interventions

PHI-101 administration DRUG

Escalated doses of PHI-101 will be administered to each cohort.

Also known as: PHI-101

Cohort 1 (PHI-101 40mg/day); Cohort 2 (PHI-101 80mg/day); Cohort 3 (PHI-101 120mg/day); Cohort 4 (PHI-101 160mg/day); Cohort 5 (PHI-101 200mg/day); Cohort 6 (PHI-101 240mg/day)

Eligibility Criteria

• Age: 19 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Females aged ≥ 19 years at the time of informed consent
• Pregnancy (childbearing potential and planning a pregnancy) and breast-feeding status ① Women of non-childbearing potential, women who are not pregnant or breast-feeding, or women who are not planning a pregnancy during the study
• ② Women of childbearing potential (Section 10.3.2.7.1) who have a confirmed negative pregnancy test at screening and immediately before administration of PHI-101 and agree to use an effective contraceptive method(s) (Section 10.3.2.7.2) required in this protocol for 6 months (24 weeks) from the last dose of PHI-101
• Indication
• ① Histologically or cytologically confirmed ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer
• ② Epithelial malignant tumors diagnosed through local histopathological findings \[WHO Histological Classification, 2014\]
• : except LGSC, mucinous carcinoma of the ovary, MMMT, and LAP, which are classified as LCOH, \[NCCN Guideline version 2.2019\].
• LAP = low malignant potential (ovarian borderline epithelial tumor); LCOH = less common ovarian histopathology; LGSC = low-grade serous carcinoma; MMMT = malignant mixed Mullerian tumor (carcinosarcoma); NCCN Guideline = National Comprehensive Cancer Network Guideline; WHO Histological Classification = World Health Organization Histological Classification ③ Platinum-refractory cancer\* or platinum-resistance cancer†
• Disease progression during platinum-based antineoplastic therapy, † Disease progression within 6 months (24 weeks) from completion of platinum-based antineoplastic therapy ④ Inoperable subjects who are refractory to, cannot receive, or refuse standard of care, which is currently known to be clinically beneficial ⑤ Subjects with ≥ 1 measurable lesion or nonmeasurable, but evaluable lesion that meets \[RECIST version 1.1\] RECIST = Response Evaluation Criteria in Solid Tumors
• Expected life expectancy ≥ 12 weeks
• \[ECOG PS\] ≤ 1 ECOG PS = Eastern Cooperative Oncology Group Performance Status
• Subjects who have adequate hepatic, renal, and hematological function confirmed by the following laboratory tests (a re-test will be allowed during the screening period) ANC ≥ 1,500/mm3 (without administration of G-CSF within 2 weeks prior to baseline) Hb ≥ 10.0 g/dL (without transfusion within 2 weeks prior to baseline) Platelet count ≥ 75,000/mm3 (without transfusion within 2 weeks prior to baseline) Total bilirubin ≤ 1.5 x ULN AST and ALT ≤ 3.0 x ULN\* (≤ 5 x ULN for patients with liver metastases or hepatocellular carcinoma) Serum creatinine (or CrCl) Serum creatinine ≤ 1.5 x ULN CrCl ≥ 60 mL/min (by Cockcroft-Gault equation)
• Prior antineoplastic therapy and treatment ① Prior cytotoxic chemotherapy ≤ 5 times
• ② Reversible side effects from prior antineoplastic therapy (operation, drug, radiation therapy, etc.)\* resolved to \[CTCAE version 5.0\] grade 1 or better
• \* Subjects should not have had major surgery, antineoplastic therapy or experimental therapy, or direct radiation therapy on hematopoietic site within 4 weeks prior to baseline and should not be administered nitrosoureas or mitomycin-C within 6 weeks prior to baseline.

You may not qualify if:

• \) Subjects with known or suspected hypersensitivity or intolerance to the active ingredient or excipients of PHI-101 2) Subjects considered ineligible or unable to participate in this study according to the investigator's judgement for other reasons
• Medical history or current medical condition and disease 3) Subjects with the following cardiac insufficiency or cardiovascular disease (but not limited to):
• Evidence of myocardial ischemia or myocardial infarction within 12 weeks prior to baseline
• \[NYHA Functional Classification\] ≥ II NYHA = New York Heart Association ③ LVEF \< 50% confirmed by ECHO or MUGA scan LVEF = left ventricular ejection fraction; ECHO = echocardiography; MUGA = Multi-gated acquisition blood pool scintigraphy
• Clinically significant cardiac arrhythmia that is uncontrolled by the adequate and optimal treatments
• ⑤ Corrected QT (QTc)\* interval \> 450 msec (for both men and women) or long QT syndrome (or family history)
• \* QT interval (QTcF) corrected using Fridericia's formula will be used. In case of bundle branch block, the Bazett's formula will be used (QTcB).
• \) Subjects with the following gastrointestinal diseases that affect intake or absorption of the drug (but not limited to):
• Dysphagia
• Paralysis of intestine and intestinal obstruction
• ③ Gastrointestinal surgery that has a clinically significant effect on absorption of the drug: gastrotomy, small intestinal fistula, extensive small bowel resection, etc. (except for simple anastomosis)
• ④ Autoimmune or inflammatory disease that involves the entire gastrointestinal system or small intestines: coeliac disease, intestinal graft versus host disease, Behcet's syndrome, scleroderma involving the gastrointestinal tract, Crohn's disease, ulcerative colitis, etc.
• \) Lung diseases (but not limited to):
• New or progressive dyspnea, cough, and fever
• ② Planned diagnosis of interstitial lung disease, or interstitial pneumonia

Sponsors & Collaborators

• Seoul National University Hospital: lead
• Pharos iBio Co., Ltd.: collaborator

Study Sites (1)

Seoul National University Hospital

Seoul, South Korea

RECRUITING

Related Publications (9)

• Suh DH, Chang SJ, Song T, Lee S, Kang WD, Lee SJ, Roh JW, Joo WD, Yoon JH, Jeong DH, Kim HS, Lee SJ, Ji YI, Kim HJ, Lee JW, Kim JW, Bae DS. Practice guidelines for management of ovarian cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement. J Gynecol Oncol. 2018 Jul;29(4):e56. doi: 10.3802/jgo.2018.29.e56. Epub 2018 Mar 10.

  PMID: 29770626 BACKGROUND

• Stover EH, Konstantinopoulos PA, Matulonis UA, Swisher EM. Biomarkers of Response and Resistance to DNA Repair Targeted Therapies. Clin Cancer Res. 2016 Dec 1;22(23):5651-5660. doi: 10.1158/1078-0432.CCR-16-0247. Epub 2016 Sep 27.

  PMID: 27678458 BACKGROUND

• Gadducci A, Guarneri V, Peccatori FA, Ronzino G, Scandurra G, Zamagni C, Zola P, Salutari V. Current strategies for the targeted treatment of high-grade serous epithelial ovarian cancer and relevance of BRCA mutational status. J Ovarian Res. 2019 Jan 28;12(1):9. doi: 10.1186/s13048-019-0484-6.

  PMID: 30691488 BACKGROUND

• Scambia G, Ferrandina G. A turning point in the fight against ovarian cancer? Lancet Oncol. 2018 Feb;19(2):154-156. doi: 10.1016/S1470-2045(18)30005-6. Epub 2018 Jan 18. No abstract available.

  PMID: 29361471 BACKGROUND

• Obeidat B, Latimer J, Crawford R. Can optimal primary cytoreduction be predicted in advanced stage epithelial ovarian cancer? Role of preoperative serum CA-125 level. Gynecol Obstet Invest. 2004;57(3):153-6. doi: 10.1159/000076236. Epub 2004 Jan 15.

  PMID: 14726621 BACKGROUND

• Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73-112. doi: 10.1016/B978-0-12-380888-2.00003-0.

  PMID: 21034966 BACKGROUND

• Jung KW, Won YJ, Kong HJ, Lee ES. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2016. Cancer Res Treat. 2019 Apr;51(2):417-430. doi: 10.4143/crt.2019.138. Epub 2019 Mar 18.

  PMID: 30913865 BACKGROUND

• McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996 Jan 4;334(1):1-6. doi: 10.1056/NEJM199601043340101.

  PMID: 7494563 BACKGROUND

• Park SJ, Chang SJ, Suh DH, Kong TW, Song H, Kim TH, Kim JW, Kim HS, Lee SJ. A phase IA dose-escalation study of PHI-101, a new checkpoint kinase 2 inhibitor, for platinum-resistant recurrent ovarian cancer. BMC Cancer. 2022 Jan 3;22(1):28. doi: 10.1186/s12885-021-09138-z.

  PMID: 34980026 DERIVED

MeSH Terms

Interventions

PHI-101

Study Officials

• Hee Seung Kim, MD

  Seoul National University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hee Seung Kim, MD

CONTACT

+82-2-2072-4863; bboddi0311@gmail.com

Soo Jin Park, MD

CONTACT

+82-2-2072-4863; soojin.mdpark@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: According to the accelerated 3+3 design, the accelerated dose escalation scheme, which assesses DLT in 1 subject in each cohort, is applied until an adverse drug reaction (ADR) ≥ \[CTCAE version 5.0\] grade 2 occurs. If an ADR ≥ grade 2 occurs in a specific cohort, the accelerated 3+3 design will be immediately switched to the standard 3+3 scheme, and 3 to 6 subjects will be enrolled in each cohort. If a DLT is observed in \> 1 out of 6 subjects in a specific cohort (χ) and a DLT is observed in ≤ 1 out of 6 subjects in the cohort (χ-1) that is one level lower than the specific cohort, the one level lower cohort (χ-1) will be considered as the MTD. The dose of PHI-101 will be escalated until an MTD is determined. If the MTD is not determined at the MPD, dose escalation will be ended at that dose.

Study Record Dates

• First Submitted: November 29, 2020
• First Posted: December 21, 2020
• Study Start: December 17, 2020
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: June 26, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)