Safety and Efficacy Study of CFI-402411 in Subjects With Advanced Solid Malignancies

The purpose of this study is to test the safety of an investigational drug called CFI-402411 alone and in combination with pembrolizumab and to study its effects in patients with advanced solid tumors who have progressed following previous therapies.

This study will be a first-in-human study evaluating the safety and tolerability of CFI-402411 in subjects with advanced solid malignancies, when CFI-402411 is administered as a single agent or in combination with pembrolizumab. CFI-402411 is an oral pill that blocks the function of HPK1. Blocking HPK1 could stimulate an immune response against the tumor in patients. This immune response could be further enhanced when combined with pembrolizumab. The data obtained from this study will determine the dose and schedule and subject selection for further clinical studies.

Pre-clinical findings support further development of CFI-402411 as a novel anti-cancer agent, and the combination of CFI-402411 with pembrolizumab as a potential strategy to improve outcomes of subjects with advanced malignancies.

Eligibility Criteria:
Key Inclusion Criteria: Study-Wide Eligibility (Across All Study Parts):

1. Age \> 18 years old
2. Have progressed after ≥ 1, but no more than 3 regimens of systemic therapies for recurrent / metastatic disease.
3. Subjects must have measurable disease.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Part A1: Monotherapy Dose Escalation Inclusion Criteria

1. Histological or cytological confirmation of advanced solid malignancy that is refractory to or not a candidate for current standard treatment(s) and for whom no standard therapy is available.

Part A2: Biomarker-Focused Monotherapy Backfills Inclusion Criteria

1. Histological or cytological confirmation of one of the advanced cancers listed below;

   * NSCLC
   * SCLC
   * cutaneous melanoma
   * Merkel cell carcinoma
   * squamous cell carcinoma of head and neck, anal canal, or skin
   * urothelial cancer
   * clear cell or non-clear cell renal cell carcinoma
   * triple negative breast cancer
   * endometrial cancer (regardless of MSI status)
   * cervical cancer
   * gastroesophageal cancer
   * hepatocellular cancer
   * any histology if known to be microsatellite-instability high (MSI-H)
2. Tumors must be refractory to or not a candidate for current standard treatment(s) and for whom no standard therapy exists.

Part A3: Monotherapy Expansion Inclusion Criteria

1. Histological or cytological confirmation of one of the advanced cancers listed below;

   * NSCLC cancer any histology
   * SCLC
   * cutaneous melanoma
   * Merkel cell carcinoma
   * squamous cell carcinoma of head and neck, anal canal, or skin
   * urothelial cancer
   * clear cell or non-clear cell renal cell carcinoma
   * triple negative breast cancer
   * endometrial cancer (regardless of MSI status)
   * cervical cancer
   * gastroesophageal cancer
   * hepatocellular
   * any histology if known to be microsatellite-instability high (MSI-H)
2. Tumors must be refractory to or subjects intolerant of current standard treatment(s) and for whom no standard therapies are available.
3. Optional biopsies: Subjects that consent to optional fresh tumor biopsies must have at least one non-target soft tissue tumor lesion that can be biopsied.

Part B1: CFI-402411 in Combination with Pembrolizumab Dose Escalation Inclusion Criteria

1. Subjects must be deemed eligible by the Investigator to receive pembrolizumab.
2. Histological or cytological confirmation of one of the advanced cancers listed below (list may vary in each country, USA shown here);

   * NSCLC cancer any histology
   * SCLC
   * cutaneous melanoma
   * Merkel cell carcinoma
   * squamous cell carcinoma of head and neck, anal canal, or skin
   * urothelial cancer
   * clear cell or non-clear cell renal cell carcinoma
   * triple negative breast cancer
   * endometrial cancer (regardless of MSI status)
   * cervical cancer
   * gastroesophageal cancer
   * hepatocellular cancer
   * any histology if known to be microsatellite-instability high (MSI-H)

Tumors must be refractory to or subjects intolerant of current standard treatment(s) or for whom no standard therapy is available.

Part B2: CFI-402411 in Combination with Pembrolizumab Expansion Inclusion Criteria

1. Subjects must be deemed eligible by the Investigator to receive pembrolizumab
2. Histological or cytological confirmation of one of the advanced cancers listed below (list may vary in each country, USA shown here);

   * non-small cell lung cancer any histology
   * SCLC
   * cutaneous melanoma
   * Merkel Cell carcinoma
   * squamous cell carcinoma of head and neck, anal canal, or skin
   * urothelial cancer
   * clear cell or non-clear cell renal cell carcinoma
   * triple negative breast cancer
   * endometrial cancer (regardless of MSI status)
   * gastroesophageal cancer
   * hepatocellular cancer
   * any histology if known to be microsatellite-instability high (MSI-H)
3. Tumors must be refractory to or subjects intolerant of current standard non-IO treatment(s) or for whom no standard therapy is available.

Key Exclusion Criteria: Study-Wide Eligibility (Across All Study Parts)

Subjects will be excluded from the study if any of the following criteria is met;

1. Previous treatment with an HPK1 inhibitor in other clinical trials.
2. Diagnosis of autoimmune-based disease or clinically significant auto-immune disorders.
3. Have symptomatic congestive heart failure, active angina pectoris or recent myocardial infarction (within 6 mos).
4. Have chronic atrial fibrillation.
5. Known central nervous system metastasis.
6. Stroke or transient ischemic attack, or other ischemic events or thromboembolic events within 3 months of study enrollment.
7. A history of QTc prolongation or a marked baseline prolongation of QT/QTc interval or a history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).