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.

Eligibility Criteria:
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)