Study Of COTI-2 As Monotherapy Or Combination Therapy For The Treatment Of Malignancies

Study Overview

Study of COTI-2 as Monotherapy or Combination Therapy for the Treatment of Malignancies

Activity of COTI-2 has been demonstrated in various cancer tumor models. With its p53- and AKT-based mechanisms of action, COTI-2 is anticipated to be highly relevant in treatment of patients with gynecologic malignancies or head and neck squamous cell carcinoma (HNSCC) as well as a variety of other tumor types. This study is designed primarily to assess the safety and tolerability of COTI-2 monotherapy or combination therapy in patients with advanced and recurrent malignancies to establish a recommended Phase 2 dose (RP2D) for future studies. Patients are currently being recruited for Part 3 of the study. Critical Outcome Technologies Inc. has been renamed to Cotinga Pharmaceuticals.

This is a three-part, multi-center, open-label, Phase 1, first-in-patient study of COTI-2 in patients with recurrent ovarian, fallopian tube, primary peritoneal, endometrial, or cervical cancer (collectively gynecological malignancies), and in patients with head and neck squamous cell carcinoma (HNSCC), colorectal, lung, or pancreatic cancer. Other tumor types may be allowed with Sponsor approval. COTI-2 will be self-administered as a single agent, orally, once daily for 5 days followed by 2 treatment-free days each week. Part 1 of the study will be dose finding in patients with gynecological malignancies using a 3 + 3 design to establish the MTD (maximum tolerated dose) over 6 planned cohorts. Part 2 of the study will be dose finding in patients with HNSCC using a 3 + 3 design to establish the MTD over 6 planned cohorts. Part 3 of the study will be dose finding for COTI-2 in combination with cisplatin in patients with gynecological malignancies, HNSCC, colorectal, lung, pancreatic cancer, or other tumor types with Sponsor approval.

Ovarian Cancer
Fallopian Tube Cancer
Endometrial Cancer
Cervical Cancer
Peritoneal Cancer
Head and Neck Cancer
HNSCC
Colorectal Cancer
Lung Cancer
Pancreatic Cancer

DRUG: COTI2
DRUG: Cisplatin

COTI2-101

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2015-04-27	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2019-01-30
First Submitted that Met QC Criteria 2015-04-29	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2019-02-01
First Posted (ACTUAL) 2015-05-05	Results First Posted N/A	Last Verified 2019-01

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: COTI2 COTI-2 will be self-administered as a single agent, orally, once daily for 5 days followed by 2 treatment-free days each week; 1 cycle will be defined as 4 weeks of treatment as described (5 days on, 2 days off per week). Participants will remain on treat	DRUG: COTI2 COTI-2 is a third generation thiosemicarbazone. DRUG: Cisplatin Cisplatin is approved to treat a range of solid tumors and lymphomas.
EXPERIMENTAL: COTI2 + cisplatin COTI-2 will be self-administered as a single agent, orally, once daily for 5 days followed by 2 treatment-free days each week; 1 cycle will be defined as 3 weeks of treatment as described (5 days on, 2 days off per week). Cisplatin 60 mg/m2 IV will be adm	DRUG: COTI2 COTI-2 is a third generation thiosemicarbazone. DRUG: Cisplatin Cisplatin is approved to treat a range of solid tumors and lymphomas.

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: COTI2

COTI-2 will be self-administered as a single agent, orally, once daily for 5 days followed by 2 treatment-free days each week; 1 cycle will be defined as 4 weeks of treatment as described (5 days on, 2 days off per week). Participants will remain on treat

DRUG: COTI2

COTI-2 is a third generation thiosemicarbazone.

DRUG: Cisplatin

Cisplatin is approved to treat a range of solid tumors and lymphomas.

EXPERIMENTAL: COTI2 + cisplatin

COTI-2 will be self-administered as a single agent, orally, once daily for 5 days followed by 2 treatment-free days each week; 1 cycle will be defined as 3 weeks of treatment as described (5 days on, 2 days off per week). Cisplatin 60 mg/m2 IV will be adm

DRUG: COTI2

COTI-2 is a third generation thiosemicarbazone.

DRUG: Cisplatin

Cisplatin is approved to treat a range of solid tumors and lymphomas.

Primary Outcome Measures	Measure Description	Time Frame
Number of dose limiting Toxicities	Used to measure safety and tolerability of COTI2	12 months
Tmax	To determine maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D)	6 months

Secondary Outcome Measures	Measure Description	Time Frame
Clinical response	This will be assessed through CT imaging, measurement using RECIST 1.0 criteria and GCIG criteria (if applicable)	6 Months
Progression Free survival	This will be assessed through CT imaging and measurement using RECIST 1.0 criteria.	12 months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Richard Ho, MD-PhD

Phone Number:

Email: rho@cotingapharma.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Part 1: Ovarian, fallopian tube, primary peritoneal, endometrial, or cervical cancer
Part 2: HNSCC, with confirmed p53 mutations
Part 3: Gynecological malignancies, HNSCC, colorectal, lung, pancreatic cancer, or other tumors with Sponsor approval. 4. Ability to attend all scheduled study visits 5. Measurable disease by physical examination or imaging as defined by RECIST v1.1 criteria or evaluable disease as defined by Gynecologic Cancer Intergroup (GCIG) CA125 criteria. 6. European Cooperative Oncology Group (ECOG) performance status 0 or 1. 7. Life expectancy ≥3 months. 8. Adequate bone marrow, liver, renal, and cardiac function at study entry, assessed as follows:

Hemoglobin ≥9.0 g/dL;
Absolute neutrophil count (ANC) ≥1.5 x 109/L;
Platelet count ≥100 x 109/L;
Prothrombin time (PT) or international normalize rate (INR) within 1.5x upper limit of normal;
Partial thromboplastin time (PTT) within 1.5x upper limit of normal;
Total bilirubin within normal limits;
Alanine transaminase (ALT) and aspartate transaminase (AST) within 1.5x upper limit of normal;
Calculated creatinine clearance >50 mL/min;
Urine protein <500 mg or urine protein: creatinine ratio (UPC) <1.0; and
Left ventricular ejection fraction (LVEF) ≥55% (or the institutional lower limit of normal [LLN]) as evidenced on ECHO. 9. Prior chemotherapy, other investigational agents, or radiation must be discontinued for at least 28 days prior to the first administration of COTI-2. Hormone treatments must be discontinued for at least 28 days prior to the first administration of COTI-2. 10. Toxicity from prior therapy (except alopecia) has resolved to ≤Grade 1; in the event of toxicity that has not resolved to ≤Grade 1 but is considered stable, the patient may be eligible after discussion among the investigator and sponsor's medical monitor. 11. Physiologically incapable of becoming pregnant, postmenopausal, or negative pregnancy test and agree to use adequate contraception (e.g., oral contraceptive, double barrier method, intra-uterine device, intra-muscular contraceptive). 12. Patients enrolled in the expansion phase must be willing to undergo pre and post-Cycle 1 biopsies. 13. Patients enrolled in the escalation and expansion phases will be required to have archival tissue available for analysis.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

M.D. Anderson Cancer Center
Northwestern Memorial Hospital

Investigators

PRINCIPAL_INVESTIGATOR: Shannon Westin, MD, MD Anderson

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Andrews S, von Gruenigen VE. Management of the late effects of treatments for gynecological cancer. Curr Opin Oncol. 2013 Sep;25(5):566-70. doi: 10.1097/CCO.0b013e328363e11a.
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011 Jun 29;474(7353):609-15. doi: 10.1038/nature10166.
Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006 Oct 1;66(19):9339-44. doi: 10.1158/0008-5472.CAN-06-3126. Epub 2006 Sep 21. No abstract available.
Creasman WT, Odicino F, Maisonneuve P, Quinn MA, Beller U, Benedet JL, Heintz AP, Ngan HY, Pecorelli S. Carcinoma of the corpus uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006 Nov;95 Suppl 1:S105-43. doi: 10.1016/S0020-7292(06)60031-3. No abstract available.
Dellinger TH, Monk BJ. Systemic therapy for recurrent endometrial cancer: a review of North American trials. Expert Rev Anticancer Ther. 2009 Jul;9(7):905-16. doi: 10.1586/era.09.54.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012 Jun 15;26(12):1268-86. doi: 10.1101/gad.190678.112.
Hirte HW, Strychowsky JE, Oliver T, Fung-Kee-Fung M, Elit L, Oza AM. Chemotherapy for recurrent, metastatic, or persistent cervical cancer: a systematic review. Int J Gynecol Cancer. 2007 Nov-Dec;17(6):1194-204. doi: 10.1111/j.1525-1438.2007.00900.x. Epub 2007 Jun 1.
Kalsi JK, Manchanda R, Menon U. Screening for gynecological cancers. Expert Rev Obstet Gynecol 2013;8(2):143-60.
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MDM, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L. Mutational landscape and significance across 12 major cancer types. Nature. 2013 Oct 17;502(7471):333-339. doi: 10.1038/nature12634.
Leary A, Auclin E, Pautier P, Lhommé C. The PI3K/Akt/mTOR pathway in ovarian cancer: biological rationale and therapeutic opportunities. In: Ovarian cancer - a clinical and translational update. InTech; 2013, pp. 275-302.
Maleki Vareki S, Salim KY, Danter WR, Koropatnick J. Novel anti-cancer drug COTI-2 synergizes with therapeutic agents and does not induce resistance or exhibit cross-resistance in human cancer cell lines. PLoS One. 2018 Jan 24;13(1):e0191766. doi: 10.1371/journal.pone.0191766. eCollection 2018.

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