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 anticancer therapies (Phase 1b) in adult participants with advanced relapsed and/or refractory solid tumors (including but not limited to CNS tumors in Phase 1a only). Phase 1b will include the following cohorts 1) tumor-specific cohorts for participants with advanced relapsed and/or refractory ovarian cancer, endometrial cancer, and cholangiocarcinoma, 2) a randomized cohort for participants with ovarian cancer who will receive PHST001 in combination with mirvetuximab soravtansine, 3) a cohort for participants with advanced/metastatic breast cancer who will receive PHST001 in combination with trastuzumab deruxtecan and 4) a cohort of patients who consent to additional biomarker studies.
The study's primary objectives are to evaluate the safety and tolerability of PHST001 and determine the RP2D (Recommended Phase 2 dose) of PHST001 as monotherapy and in combination with anticancer therapies, as well as to assess the anti-tumor activity of PHST001 in combination with anticancer therapies in Phase 1b.
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
Diagnosis of immunodeficiency
History of a previous additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 2 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, low grade neoplasms, 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 from a systemic (non-CNS) primary malignancy. Participants with previously treated CNS metastases are eligible, provided they are radiologically and clinically stable (i.e., no evidence of progression for at least 2 weeks by repeat imaging performed during screening) and are not requiring systemic corticosteroids above the physiologic replacement for at least 7 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.
Sequential
PHST001
Biological/VaccinePHST001 is an anti-CD24 macrophage checkpoint inhibitor, administered as IV infusions every 3-weeks (Q3W) dosing intervals.
Paclitaxel
DrugPaclitaxel used as per standard of care.
Topotecan
DrugTopotecan used as per standard of care.
Doxorubicin
DrugDoxorubicin used as per standard of care.
FOLFIRI
DrugFOLFIRI used as per standard of care.
FOLFOX
DrugFOLFOX used as per standard of care.
Gemcitabine
DrugGemcitabine used as per standard of care.
Mirvetuximab Soravtansine
Biological/VaccineMirvetuximab soravtansine used as per standard of care.
Trastuzumab Deruxtecan
Biological/VaccineTrastuzumab deruxtecan used as per standard of care.
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Treatment groupsSee each treatment group below.
Frequency of Dose-Limiting Toxicities (DLTs) to assess the safety and tolerability of PHST001 as monotherapy (Phase 1a) or in combination with anticancer therapy (Phase 1b)
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 anticancer therapy (Phase 1b)
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 anticancer therapy (Phase 1b)
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 anticancer therapy (Phase 1b)
Based on toxicities observed
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) and in combination with anticancer therapy (Phase 1b - randomized cohort only)
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) and in combination with anticancer therapy (Phase 1b)
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) and in combination with anticancer therapy (Phase 1b)
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) and in combination with anticancer therapy (Phase 1b - non-randomized cohorts only) .
Defined as the time from first dose of PHST001 to first documentation of radiographic disease progression or death, whichever occurs first.
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