Advanced Solid Malignancies
Conditions
Keywords
advanced tumors, pembro, keytruda, pembrolizumab, 2411, CFI-402411, first in human, first-in-human, hematopoietic progenitor kinase-1 inhibitor, HPK1, advanced solid malignancies, solid malignancies, TWT-101, TWT101, UHN, University Health Network, Treadwell Therapeutics
Brief summary
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.
Detailed description
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.
Interventions
DRUGCFI-402411
CFI-402411 is administered orally once daily. The starting dose is 80 mg/day for escalation arms and the recommended dose for the expansion arms.
DRUGPembrolizumab
Pembrolizumab will be given at its labeled dose and schedule, 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.
Sponsors
TIO Discovery Engine
Treadwell Therapeutics, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation and expansion for monotherapy and combination arms with pembrolizumab
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess the incidence of adverse events of CFI-402411 as a single agent and at the recommended phase 2 dose (RP2D). | 48 months | The number of subjects who experience an adverse event that was possibly related to study drug. |
| To assess the incidence of adverse events with CFI-402411 in combination with pembrolizumab and at the RP2D. | 48 months | The number of subjects who experience an adverse event that was possibly related to study drug. |
| To examine best overall response rate in subjects treated at multiple dose levels of CFI-402411. | 48 months | Best overall response rate will be summarized by dose cohort and overall using the percent of patients in each tumor response category. |
| To examine progression free survival in subjects treated at multiple dose levels of CFI-402411. | 48 months | Time from first dose to disease progression or death whichever occurs first will be calculated and summarized for all patients by dose cohort and overall. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess overall survival of CFI-402411 monotherapy and in combination with pembrolizumab. | 48 months | The time from first dose until the date of death from any cause will be calculated and summarized for all patients by dose cohort and overall. |
| To assess progression free survival of CFI-402411 monotherapy and in combination with pembrolizumab. | 48 months | Time from first dose to disease progression or death whichever occurs first will be calculated and summarized for all patients by dose cohort and overall. |
| To assess duration of response of CFI-402411 monotherapy and in combination with pembrolizumab. | 48 months | The time from the first objective response to the time of documented disease progression or death due to any cause, whichever occurs first, will be calculated and summarized for all patients by dose cohort and overall. |
| To assess the pharmacokinetic profile of CFI-402411 alone when it is administered in combination with pembrolizumab through AUC. | 48 months | Area under the plasma concentration (AUC) versus time curve from time 0 to time of least measurable concentration tabulated by dose group. |
| To identify the maximum tolerated dose of single agent CFI-402411 alone and in combination with pembrolizumab. | 48 months | Safety tables and pharmacokinetic tables will be assessed. |
| To assess the pharmacokinetic profile of CFI-402411 alone when it is administered in combination with pembrolizumab through Tmax. | 48 months | Tmax will be assessed by the time to achieve maximum plasma concentration and will be tabulated by dose group. |
| To assess the pharmacokinetic profile of CFI-402411 alone when it is administered in combination with pembrolizumab though Cmin. | 48 months | Cmin will be calculated through the measured pre-dose plasma concentration and tabulated by dose group. |
| To assess the pharmacokinetic profile of CFI-402411 alone when it is administered in combination with pembrolizumab through T1/2. | 48 months | Elimination half life will be calculated and tabulated by dose group. |
| To evaluate the effect of CFI-402411 treatment on immune- or disease related biomarkers. | 48 months | The effects of CFI-402411 on pharmacodynamic biomarkers (cytokine levels) will be assessed by percent changes from baseline. |
| To assess the pharmacokinetic profile of CFI-402411 alone when it is administered in combination with pembrolizumab through Cmax. | 48 months | Cmax will be assessed through the maximum measured plasma concentration occurring at Tmax tabulated by dose group. |
| To further assess the incidence of adverse events of CFI-402411. | 48 months | The number of subjects who experience an adverse event that was possibly related to study drug. |
| To assess best overall response of CFI-402411 monotherapy and in combination with pembrolizumab. | 48 months | Best overall response rate will be summarized by dose cohort and overall using the percent of patients in each tumor response category. |
| To assess overall response rates of CFI-402411 monotherapy and in combination with pembrolizumab. | 48 months | For all subjects the overall response rates of complete response and partial response will be calculated and summarized by dose cohort and overall. |
Countries
Canada, Hong Kong, United States
Outcome results
None listed