Dose Escalation/Expansion Study of PT199 (an Anti-CD73 MAb) Administered Alone and in Combination with a PD-1 Inhibitor or Chemotherapy (the MORNINGSTAR Study)

Phanes Therapeutics

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Pancreatic Ductal Adenocarcinoma; Non Small Cell Lung Cancer

Treatments: Drug: Pemetrexed; Drug: Carboplatin + Pemetrexed; Drug: PT199; Drug: Pembrolizumab + Carboplatin + Pemetrexed; Drug: Tislelizumab; Drug: Docetaxel; Drug: Gemcitabine; Drug: Gemcitabine + nab-Paclitaxel

Study type: Interventional

Funder types: Industry

Identifiers

NCT05431270

PT199X1101

Details and patient eligibility

About

This is a first-in-human, Phase 1/2, open-label, study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PT199 alone and in combination with a PD-1 inhibitor or chemotherapy.

Full description

PT199 is an anti-CD73 mAb with a differentiated mechanism of action and is expected to completely inhibit CD73 enzyme activity. PT199 is designed to counter the adenosine-mediated immunosuppressive tumor microenvironment, rendering anti-tumor immune cells to be more active and more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors.

CD73 is widely overexpressed in a number of different cancers, including pancreatic ductal adenocarcinoma (PDAC), gastric carcinoma, colorectal carcinoma, non-small cell lung cancer (NSCLC), sarcomas and glioblastomas. Thus, targeting CD73 may provide benefit for patients with a high CD73 expression in their tumor.

PT199 addresses the limitations of current CD73 inhibitors and is expected to increase antitumor immune activation, especially in combination with PD-1 pathway inhibition, and thus offer a new treatment option for cancer patients.

NSCLC is known to have a high expression level of CD73, and emerging clinical data has shown that targeting CD73 may provide clinical benefit, when combined with an immune checkpoint inhibitor (ICI) and/or standard of care chemotherapies to overcome treatment resistance.

Enrollment: 40 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria

1. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors.

2. For Part A: a histologically or cytologically confirmed unresectable advanced or metastatic solid tumors previously treated with therapies, or for which treatment is not available or not tolerated.

   For Part B: A histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations and radiological documentation of disease progression on prior treatments, which may include a checkpoint inhibitor, or patients diagnosed with metastatic and/or advanced (m/a) PDAC who have disease progression after previously treated with therapies, or for which treatment is not available or not tolerated.

   For Part C: A histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations such as EGFR or ALK mutations and radiological documentation of disease progression on prior treatments, which may include a checkpoint inhibitor.

   For Part D:

   • Cohort D1: a histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma (PDAC), treatment naïve for advanced or metastatic disease, and eligible to receive standard of care treatment with gemcitabine plus nab-paclitaxel.
   • Cohort D2: a histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations and radiological documentation of disease progression on prior treatments, which may include a checkpoint inhibitor. Patients have progressed under first-line (1L) SOC chemotherapy with or without ICI or later lines of therapy, or for which standard 1L therapy has proven to be ineffective, intolerable, or is considered inappropriate.
   • Cohort D3: a histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations. Patients are treatment naïve and have no contra indication to receive carboplatin plus pemetrexed.
   • Cohort D4: a histologically or cytologically confirmed diagnosis of NSCLC without actionable genomic alterations (AGAs) such as EGFR or ALK mutations. Patients are treatment naïve and are eligible for 1L therapy with pembrolizumab and carboplatin plus pemetrexed.

3. In all Parts, should be able to provide a tumor tissue sample (archival or newly acquired biopsy) to be assessed for CD73 and other biomarkers (PD-L1), unless deemed by the Investigator to cause risk to the patient or per Investigator's discretion.

4. ECOG performance status of 0 or 1.

5. Adequate organ function confirmed at screening and within 72 hours of initiating treatment.

Key Exclusion Criteria

1. Women who are pregnant or lactating.
2. Women of child-bearing potential (WOCBP) who do not use adequate birth control.
3. Autoimmune disease requiring systemic treatment within the past twelve months. Active autoimmune disease or a history of autoimmune diseases that may relapse.
4. Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to study treatment.
5. Patients who have experienced Grade ≥ 3 immune-related events, such as (non-infectious) pneumonitis, interstitial lung disease, myocarditis.
6. Patients with untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed.
7. Impaired cardiac function or significant diseases.
8. Patients who have ≥ Grade 3 neuropathy.
9. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy.
10. Patients who are currently receiving (last dose within 5 days from C1D1) treatment with therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants.

Additional inclusion and exclusion criteria will apply.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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40 participants in 4 patient groups

Part A: Monotherapy Dose Escalation

Experimental group

Description:

A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. PT199 will be administered as a monotherapy.

Treatment:

Drug: PT199

Part B: Combination Therapy Dose Escalation

Experimental group

Description:

A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. Patients will be treated with PT199 in combination with a PD-1 inhibitor, tislelizumab.

Treatment:

Drug: Tislelizumab

Drug: PT199

Part C: Combination Therapy Dose Expansion

Experimental group

Description:

Two RDEs for Part C will be determined in Part B and will be further evaluated in two dose expansion cohorts. Patients will be treated with PT199 in combination with a PD-1 inhibitor, tislelizumab.

Treatment:

Drug: Tislelizumab

Drug: PT199

Part D: Chemotherapy Combination

Experimental group

Description:

The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive PT199 plus chemotherapy, with one cohort also receiving pembrolizumab.

Treatment:

Drug: Gemcitabine + nab-Paclitaxel

Drug: Gemcitabine

Drug: Docetaxel

Drug: Pembrolizumab + Carboplatin + Pemetrexed

Drug: PT199

Drug: Carboplatin + Pemetrexed

Drug: Pemetrexed