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

Colorectal Cancer Clinical Trial

— COTI2-101  

Official title:

A Phase 1 Study of COTI-2 as Monotherapy or Combination Therapy for the Treatment of Advanced or Recurrent Malignancies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02433626
• Other study ID #: COTI2-101
• Status: Recruiting
• Phase: Phase 1
• Start date: December 2015
• Est. completion date: June 2020

Study information

• Verified date: January 2019
• Source: Critical Outcome Technologies Inc.
• Contact: Richard Ho, MD-PhD
• Email: rho[@]cotingapharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 51
• Est. completion date: June 2020
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

1. =18 years of age.

2. Willing and able to provide written informed consent to participate in this investigational study.

3. Cancer that is recurrent, metastatic, or unresectable and for which no effective or curative measures exist.

• 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.

Exclusion Criteria:

1. Pregnant or lactating.

2. History of other invasive malignancies, with the exception of non-melanoma skin cancer or successfully treated in situ carcinoma, if there is evidence of the malignancy being present within the last 3 years.

3. Inability to tolerate oral medications.

4. Any serious and/or unstable pre-existing medical, psychiatric, or other condition (e.g., severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.

5. History of clinically significant or uncontrolled cardiac disease including but not limited to:

1. Myocardial infarction,

2. Angina pectoris,

3. Congestive heart failure of New York Heart Association (NYHA) Grade >2,

4. Ventricular arrhythmias requiring continuous therapy, or

5. Supraventricular arrhythmias including atrial fibrillation, which are uncontrolled.

6. Major surgery, excluding skin biopsies and procedures for insertion of central venous access devices, within 28 days prior to the start of COTI-2.

7. Active, uncontrolled bacterial, viral, fungal, or other opportunistic infection requiring systemic therapy.

8. Part 2:

1. The presence of or imminent occurrence of airway obstruction, unless tracheostomy in place.

2. HPV-positive status ( In HNSCC patients only)

Related Conditions & MeSH terms

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

Intervention

Drug:
• COTI2
COTI-2 is a third generation thiosemicarbazone.
• Cisplatin
Cisplatin is approved to treat a range of solid tumors and lymphomas.

Locations

Country	Name	City	State
United States	MD Anderson Cancer Center	Houston	Texas

Sponsors (3)

Lead Sponsor	Collaborator
Critical Outcome Technologies Inc.	M.D. Anderson Cancer Center, Northwestern Memorial Hospital

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. Review. — View Citation

Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011 Jun 29;474(7353):609-15. doi: 10.1038/nature10166. Erratum in: Nature. 2012 Oct 11;490(7419):298. — View Citation

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. Epub 2006 Sep 21. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. Epub 2007 Jun 1. Review. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of dose limiting Toxicities	Used to measure safety and tolerability of COTI2	12 months
Primary	Tmax	To determine maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D)	6 months
Secondary	Clinical response	This will be assessed through CT imaging, measurement using RECIST 1.0 criteria and GCIG criteria (if applicable)	6 Months
Secondary	Progression Free survival	This will be assessed through CT imaging and measurement using RECIST 1.0 criteria.	12 months