A Study of PRT1419 in Patients With Advanced Solid Tumors

This is a multicenter, open-label, dose-escalation Phase 1 study of PRT1419, a MCL1 inhibitor, evaluating patients with relapsed or refractory solid tumors, including breast, lung, sarcoma and melanoma as part of a 28-day treatment cycle. The study will employ a "3+3" dose escalation design. The dose may be escalated until a dose limiting toxicity is identified.

• PRT1419 (Drug): PRT1419 will be administered by intravenous infusion

Primary outcomes

• Dose limiting toxicities (DLT) of PRT1419 [Baseline through Day 28]: Dose limiting toxicities will be evaluated through the first cycle
• Maximally tolerated dose (MTD) and/or optimal biological dose (OBD) [Baseline through approximately 2 years]: The MTD and/or OBD will be established for further investigation in participants with advanced solid tumors.
• Recommended phase 2 dose (RP2D) and schedule of PRT1419 [Baseline through approximately 2 years]: The RP2D will be established for further investigation in participants with advanced solid tumors.

Secondary outcomes

• Safety and tolerability of PRT1419: AEs, SAEs, CTCAE assessments [Baseline through approximately 2 years]: Safety and tolerability will be assessed by recording adverse events (AEs) and serious adverse events (SAEs) according to Common Terminology Criteria for Adverse Events (CTCAE)
• Pharmacokinetic profile of PRT1419: maximum observed plasma concentration [Baseline through approximately 2 years]: PRT1419 pharmacokinetics will be calculated including the maximum observed plasma concentration
• Anti-tumor activity of PRT1419: measurement of objective responses [Baseline through approximately 2 years]: Anti-tumor activity of PRT1419 will be based on the measurement of objective responses
• Progression-free survival [Baseline through approximately 2 years]: Progression-free survival will be calculated from the first administration of PRT1419 until death or until the criteria for disease progression are met

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
* Adequate organ function (bone marrow, hepatic, renal, cardiovascular)
* Left ventricular ejection fraction of ≥ 50%
* Female patients of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment and must agree to use a highly effective method of contraception during the trial
* Patients must have recovered from the effects of any prior cancer related therapy, radiotherapy or surgery (toxicity ≤ Grade 1)
* All patients on prior investigational agents must wait at least 5 half-lives of the agent in question, or 28 days, whichever is longer before study entry
* Most recent lab values meet the following criteria:

  * Absolute neutrophil count > 1.0 x 10\^3/μL;
  * Platelet count > 75,000/μL;
  * Hemoglobin > 9.0 g/dL
* Histologically confirmed advanced or metastatic solid tumor indicated below that is relapsed, refractory, or intolerant to available therapies with known benefit:

  * Sarcoma not amendable to curative treatment with surgery or radiotherapy;
  * Melanoma (non-resectable or metastatic);
  * Small cell lung cancer (extensive-stage);
  * Non-small cell lung cancer;
  * Triple negative breast cancer (histopathologically or cytologically confirmed).
  * Esophageal cancer
  * Cervical cancer
  * Head and neck cancer

Exclusion Criteria:

* Known hypersensitivity to any of the components of PRT1419
* Primary malignancies of the CNS, or uncontrolled CNS metastases, including impending spinal cord compression
* Female patients who are pregnant or lactating
* Inflammatory disorders of the gastrointestinal tract, or subjects with GI malabsorption
* Mean QTcF interval of >480 msec
* History of heart failure, additional risk factors for arrhythmias or requiring concomitant medications that prolong the QT/QTc interval
* HIV positive; known active hepatitis B or C
* Uncontrolled intercurrent illnesses
* Treatment with strong inhibitors of CYP2C8
* Prior exposure to an MCL1 inhibitor
* History of another malignancy except:

  * Malignancy treated with curative intent with no known active disease for >2 years at study entry;
  * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
  * Adequately treated carcinoma in situ without evidence of disease;
  * Other concurrent low-grade malignancies (i.e chronic lymphocytic leukemia (Rai 0)) may be considered after consultation with Sponsor.