Advanced Solid Tumors, Cholangiocarcinoma, CNS Tumor, Endometrial Cancer, Ovarian Cancer
Conditions
Brief summary
This is a multi-center, first-in-human (FIH), open-label, Phase 1a/1b dose escalation and dose expansion study to assess the safety, PK, pharmacodynamics, and antitumor activity of PHST001 monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) in adult participants with advanced relapsed and/or refractory solid tumors (including but not limited to CNS tumors in Phase 1a only). In Phase 1b cohort expansions, the study will focus on participants with advanced relapsed and/or refractory ovarian cancer, endometrial cancer, and cholangiocarcinoma. The study's primary objective is to evaluate the safety and tolerability of PHST001 and determine the RP2D (Recommended Phase 2 dose) of PHST001 monotherapy and in combination with chemotherapy as well as assess the anti-tumor activity of PHST001 and chemotherapy in Phase 1b.
Interventions
BIOLOGICALPHST001
PHST001 is an anti-CD24 macrophage checkpoint inhibitor, administered as IV infusions every 3-weeks (Q3W) dosing intervals.
DRUGChemotherapy per Standard of Care
Participants will receive PHST001 at a dose level and schedule based on monotherapy data in Phase 1a. PHST001 will be combined with chemotherapeutic agents used as standard of care.
Sponsors
Pheast Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose levels are 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 4.0 mg/kg, 6.0 mg/kg, 9.0 mg/kg, 18.0 mg/kg, 36.0 mg/kg alone or in combination with chemotherapy
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically or cytologically confirmed advanced solid tumor which has relapsed from or been refractory to all locally available standard therapies. * Adequate organ function per laboratory testing * Pregnancy prevention requirements * Measurable disease per RECIST v1.1 (or RANO) as assessed by the local site Investigator/radiology * Performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) scale Key
Exclusion criteria
* Diagnosis of immunodeficiency * History of a previous additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years. Participants with basal cell carcinoma of the skin, Stage I melanoma, melanoma in situ, squamous cell carcinoma of the skin, early-stage prostate cancer, or carcinoma in situ, excluding carcinoma in situ of the bladder, who have undergone potentially curative therapy are not excluded and can be enrolled regardless of disease-free period following completion of potentially curative therapy. Participants with early-stage breast cancer who have undergone curative intent treatment and with no disease recurrence for 2 years after treatment are not excluded. * Active known CNS metastases and/or carcinomatous meningitis. Participants with previously treated CNS metastases may participate provided they are radiologically stable (i.e., without evidence of progression for at least 2 weeks by repeat imaging \[note that the repeat imaging should be performed during study screening\]), clinically stable, and without requirement of steroid treatment for at least 14 days prior to the first dose of study treatment. * Received prior systemic anticancer therapy including investigational agents within 21 days or, if shorter, within 5 half-lives prior to the first dose of study treatment. Participants must have recovered from all AEs due to previous therapies to Grade ≤1 or baseline. Participants with Grade ≤2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible. * Prior autologous or allogeneic hematopoietic stem cell transplant or solid organ transplant. * Received previous treatment with another agent targeting CD24.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Dose-Limiting Toxicities (DLTs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From first dose of PHST001 through 21 days after the first dose of PHST001 | Based on toxicities observed |
| Frequency of Serious Adverse Events (SAEs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From signed consent up to 90 days after the last dose of PHST001 | Based on toxicities observed |
| Frequency of Treatment Emergent Adverse Events (TEAEs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From first dose up to 90 days after the last dose of PHST001 | Based on toxicities observed |
| Frequency of Treatment Related Adverse Events (TRAEs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From first dose up to 90 days after the last dose of PHST001 | Based on toxicities observed |
| Frequency of Adverse Events of Special Interest (AESIs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From first dose up to 90 days after the last dose of PHST001 | Based on toxicities observed |
| Frequency of AEs Leading to Dose Interruption or Treatment Discontinuation and AEs Leading to Death to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From first dose up to 90 days after the last dose of PHST001 | Based on toxicities observed |
| Overall Response Rate (ORR) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b) | From screening and during treatment up to 2 years | Defined as the proportion of subjects with confirmed complete response (CR) or partial response (PR); a confirmed response is a response that persists on repeat-imaging ≥ 4 weeks after initial documentation of response. |
| Duration of Response (DOR) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b) | From screening and during treatment up to 2 years | Defined as time from date of first objective response (either CR or PR) to first documentation of radiographic disease progression. |
| Best Overall Response (BOR) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b) | From screening and during treatment up to 2 years | Defined as the best response recorded for a participant across all time-point assessments from the start of treatment until disease progression or end of treatment. |
| Progression-Free Survival (PFS) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b) | From screening and during treatment up to 2 years | Defined as the time from first dose of PHST001 to first documentation of radiographic disease progression or death, whichever occurs first. |
| Overall Survival (OS) based on RECIST v1.1 to assess the preliminary antitumor activity of PHST001 in combination with chemotherapy (Phase 1b) | From screening and during treatment up to 2 years | Defined as the time from first dose of PHST001 to the date of death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a) | From screening and during treatment up to 2 years | Defined as the proportion of subjects with confirmed complete response (CR) or partial response (PR); a confirmed response is a response that persists on repeat-imaging ≥ 4 weeks after initial documentation of response. |
| Duration of Response (DOR) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a) | From screening and during treatment up to 2 years | Defined as time from date of first objective response (either CR or PR) to first documentation of radiographic disease progression. |
| Best Overall Response (BOR) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a) | From screening and during treatment up to 2 years | Defined as the best response recorded for a participant across all time-point assessments from the start of treatment until disease progression or end of treatment. |
| Progression-Free Survival (PFS) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a). | From screening and during treatment up to 2 years | Defined as the time from first dose of PHST001 to first documentation of radiographic disease progression or death, whichever occurs first. |
| Overall Survival (OS) based on RECIST v1.1 (or RANO for primary CNS Tumors) to assess the preliminary antitumor activity of PHST001 as monotherapy (Phase 1a). | From screening and during treatment up to 2 years | Defined as the time from first dose of PHST001 to the date of death. |
| Maximum Observed Concentration (Cmax) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b). | From treatment until 90 days after last dose of PHST001 | Defined as the maximum blood concentration of a dose of PHST001 |
| Time to Maximum Concentration (tmax) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From treatment until 90 days after last dose of PHST001 | Defined as the time required for a dose of PHST001 to reach its maximum blood concentration (Cmax) after administration. |
| Concentration at the End of a Dosing Interval (Ctrough) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From treatment until 90 days after last dose of PHST001 | Defined as the blood concentration of a dose of PHST001 at the end of the dosing interval (just prior to next drug administration). |
| Area Under the Concentration-time Curve (AUC) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From treatment until 90 days after last dose of PHST001 | Defined as the total PHST001 exposure over time, calculated as the integral of the plasma concentration-time profile. |
| Volume of Distribution at Steady-state (Vss) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From treatment until 90 days after last dose of PHST001 | Defined as how widely PHST001 spreads throughout the body once things have stabilized after a dose has been administered. |
| Clearance (CL) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From treatment until 90 days after last dose of PHST001 | Defined as the rate at which the body "cleans out" a dose of PHST001 from the bloodstream. |
| Terminal Elimination Half-life (t½) to characterize the serum PK of PHST001 as monotherapy (Phase 1a) or in combination with chemotherapy (Phase 1b) | From treatment until 90 days after last dose of PHST001 | Defined as the time it takes for the amount of PHST001 in the body to drop by half during the final phase of elimination. |
Countries
United States
Contacts
CONTACTAndrew Ferguson/VP Clinical Development, PhD
Outcome results
None listed