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Up to 12 patients, in 3+3 cohorts, all patients treated with Intra-arterial Ad-P53 once weekly, dosing dependent on DLT and MTD findings, and daily metronomic Xeloda (capecetabine), at a dose of 625 mg/m2 BID continuously.

Up to 12 patients, in 3+3 cohorts, all patients treated with Intra-arterial Ad-P53 once weekly, dosing dependent on DLT and MTD findings, and infusions of pembrolizumab every 3 weeks.

Up to 12 patients treated with intra-tumoral Ad-P53 3 times week 1 of each cycle, dose determined by tumor size, in combination with IV nivolumab (Opdivo) 480 mg, every 4 weeks.

Adenoviral Investigational Product Ad-P53 to treat metastases using an intra-arterial catheter, with oral metronomic capecitabine

Ad-P53

Xeloda

Antineoplastic, Monoclonal Antibody; PD-1/PD-L1 Inhibitors

Keytruda

Opdivo

Vivek Subbiah, MD

This is a Phase 1/2 study of the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine or pembrolizumab in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). A third arm will study the intra-tumoral injection of Ad-p53 combined with nivolumab infusions in recurrent head and neck squamous cell cancer (HNSCC). This safety study has a standard 3+3 design for arms A and B; .HNSCC will be placed in a single dosing cohort. The Maximum Tolerated Dose (MTD) will be determined as well for intra-arterial infusions, and the entire study will determine the general efficacy using RECIST 1.1 and Immune-Related Response Criteria. Safety will be followed using the CTCAE listings for adverse events.

This is a Phase 1/2 study split into 3 arms. Arm A will follow the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine while Arm B follows the intra-arterial administration of Ad-p53 combined with pembrolizumab, both in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). Arm C will follow the combination of intra-tumoral injections of Ad-p53 and nivolumab infusions. Arms A and B have a standard 3+3 design, with dosing following the initial cohort determined by MTD and DLT criteria as well as safety and tolerance. Arm C will be a single dosing cohort followed for safety and efficacy. All patients will be followed for adverse events and preliminary efficacy. In Arms A and B, the Maximum Tolerated dose (MTD) will be determined. All patients will be followed for general safety and preliminary efficacy using RECIST 1.1 and Immune-Related Response Criteria. CEA levels will also be followed for patients with metastatic colo-rectal cancer. Biomarker testing of archival or fresh tissue is performed during the study. In Arms A and B, patients will undergo a maximum of 2 8-week cycles, with scans every 8 weeks. For Arm B, patients will undergo a maximum of 3 28-day Cycles. All patients will continue on the background therapy for any additional cycles. No additional biopsies are planned following Screening. Enrollment will be up to 24 patients.

Safety and Efficacy of Intra-Arterial and Intra-Tumoral Ad-p53 With Capecitabine (Xeloda) or Anti-PD-1 in Liver Metastases of Solid Tumors and Recurrent Head and Neck Squamous Cell Cancer

Phase 1/2 Evaluation of Adenoviral p53 (Ad-p53) in Combination With Capecitabine (Xeloda) or Anti-PD-1 in Patients With Unresectable Liver Metastases of Colorectal Carcinoma(CRC) and Other Solid Tumors, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) and Primary Hepatic Cancers With Known Disease Progression on Standard Therapy

Incidence of treatment-emergent and treatment-related adverse events (all AEs, laboratory AEs, SAEs and Fatal AEs, in accordance with the CTCAE

To evaluate the safety, as assessed by the incidence of dose limiting toxicities, of the combination of Ad-P53 and Xeloda or Ad-p53 and Keytruda

Determination of maximum tolerated dose (MTD) by review of DLTs, of the combination of Ad-p53 and Xeloda or Ad-p53 and Ketruda

PFS in patients treated with Ad-p53 and nivolumab determined by review of scans every 8 weeks for disease progression in accordance with RECIST 1.1. Scans are read locally but kept for possible central review. Scans are done every 8 weeks. Sites will review questionable findings on scans with Immune Related Response Criteria (irRC) \[Wolchok 2009\].

PFS determined by review of scans every 8 weeks for disease progression in accordance with RECIST 1.1 in patients treated with Ad-p53 and either Xeloda or Keytruda. Scans are read locally but kept for possible central review. Scans are done every 8 weeks.

Efficacy will be determined by review of the irRC (Immune-Related Response Criteria. Patients will undergo scanning every 8 weeks for the duration of the study, with evaluation of the scans in accordance with the Immune Related Response Criteria, including confirmation of disease progression with a scan 4 weeks after noted per RECIST criteria.

Efficacy endpoints will be correlated with central biomarker testing for PDL-1, PD-2, as well as central biomarker testing for immune cell infiltrates and tumor mutational burden biomarkers in exploratory analyses, through Cancer Genetics, Inc.

MultiVir, Inc.

Gemcitabine

Paclitaxel

Albumin-Bound Paclitaxel

Fort part 2 the Cohort 1 will include patients with PDAC treated with the combination of PEP-010 at the dose of 2.5 mg/kg and weekly paclitaxel 80 mg/m².

In arm B, the dose escalation phase will begin with DL4 (1.2 mg/kg) and will follow a 3+3 design For part 2 Cohort 2 will include patients with PDAC or OC treated with the combination of PEP-010 in ascending doses, and gemcitabine at 1000 mg/m2.

Four doses of PEP-010 will be tested: 1.2 mg/kg, 2.5 mg/kg, 5 mg/kg and 10 mg/kg, according to a 3+3 dose escalation design.

PEP-010 will be administered on days 1, 2 and 3 every week, as a 3-hour intravenous infusion. Treatment will be administered until disease progression, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Each cycle will be of 21 days duration.

Dose escalation, first-in-human phase I clinical trial with an Expansion phase

Anne-Claire COYNE, PhD

Anne-Claire COYNE

COQUAN, MD

Elodie COQUAN, MD

Christophe Le Tourneau, MD

Christophe LE TOURNEAU, PR

HIRET, MD

Sandrine HIRET, MD

Sophie POSTEL-VINAY, MD

Christophe LE TOURNEAU, MD, PhD

This is an open-label, non-controlled, multicenter, dose escalation, first-in-human phase I clinical trial with an expansion phase designed to assess the safety, tolerability, PK and PD parameters, and preliminary antitumor activity of intravenous dosing of PEP-010 as single agent and in combination with paclitaxel or with gemcitabine

PEP-010 will be administered, in a Part 1, as single agent in patients with solid cancers who are not amenable to standard treatment, or in combination in patients who are eligible for the paclitaxel therapy, and in a Part 2 only in combination in:

Cohort 1 (expansion cohort, phase 1b): metastatic pancreatic ductal carcinoma (PDAC) who received at least one previous systemic chemotherapy and eligible for paclitaxel therapy.

Cohort 2 (dose escalation cohort, phase 1a): metastatic pancreatic ductal carcinoma or advanced/metastatic ovarian cancer (OC) eligible for gemcitabine-based therapy

Part 1 : PEP-010 was administered on days 1, 2 and 3 every week. Treatment was administered until disease progression, unacceptable toxicity, death or withdrawal of consent, whichever occured first. Each cycle was of 21 days duration.

The initial starting dose of PEP-010, DL1 was selected based on pre-clinical data at 0.15 mg/kg. The other doses per injection from DL2 to DL7 are 0.3, 0.6; 1.2; 2.5; 5; 10 and 15 mg/kg.

For patients in Arm B, PEP-010 was combined with Paclitaxel, at a dose of 80 mg/m², weekly until disease progression or unacceptable toxicity. Paclitaxel will be administered according to local guidelines.

Main objective for Dose escalation cohorts was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PEP-010 when administered as single agent (MTD1/RP2D1), and in combination with paclitaxel (MTD2/RP2D2) by recording the dose-limiting toxicities (DLTs).

Secondary objectives were

* To evaluate the safety and tolerability of PEP-010 when administered as single agent, and in combination with paclitaxel.
* To assess the pharmacokinetics (PK) of PEP-010 as single agent, and in combination with paclitaxel in Dose escalation cohorts.
* To assess the pharmacodynamic (PD) effects of PEP-010 as single agent, and in combination with paclitaxel.
* To evaluate the preliminary antitumor activity of PEP-010 alone and in combination with paclitaxel, using Objective Response Rate (ORR), Progression-Free Survival (PFS) according to RECIST1.1, duration of response, and Overall Survival (OS).
* To assess the immunogenicity of PEP-010 as single agent, and in combination with paclitaxel in Dose escalation cohorts.

Part 2 :

In Part 2 - Cohort 1, PDAC patients will receive PEP-010 at dose 2.5 mg/kg in combination with paclitaxel administered at a dose of 80 mg/m² weekly.

In Part 2 - Cohort 2, PDAC and OC patients will receive PEP-010 at doses 1.2 to 10 mg/kg (short dose escamation) in combination with gemcitabine administered at a dose of 1000 mg/m² weekly during 3 weeks followed by a week without infusion.

Main objectives for Part 2 (Cohort 1)

• To determine the efficacy of PEP-010 in combination with paclitaxel in patients with pancreatic ductal adenocarcinoma by assessment of the objective response rate.

Part 2 (Cohort 2)

* To determine the MTD of PEP-010 when administered in combination with gemcitabine.
* To determine the RP2D of PEP-010 when administered in combination with gemcitabine.

Secondary objectives for Part 2 (Cohorts 1 and 2 )

* To evaluate the safety and tolerability of PEP-010 when administered in combination with paclitaxel or with gemcitabine.
* To complete the pharmacokinetics (PK) of PEP-010 in combination with paclitaxel.
* To assess the pharmacokinetics (PK) of PEP-010 in combination with gemcitabine.
* To assess the pharmacokinetics (PK) of paclitaxel, when administered in combination with PEP-010.
* To assess the pharmacokinetics (PK) of gemcitabine, when administered in combination with PEP-010.
* To characterize the PD effects of PEP-010 in combination with paclitaxel or with gemcitabine.
* To evaluate the preliminary antitumor activity of PEP-010 in combination with paclitaxel at the RP2D in term of PFS, duration of response and OS (Cohort 1).
* To evaluate the preliminary antitumor activity of PEP-010 in combination with gemcitabine using the ORR, PFS, duration of response and OS (Cohort 2).
* To assess the immunogenicity of PEP-010 in combination with paclitaxel or gemcitabine

Part 1 dose escalation Part 2 expansion cohort and short dose escalation cohort

First-in-human Phase I to Evaluate PEP-010 as Single Agent and in Combination With Paclitaxel or With Gemcitabine (CleverPeptide)

Dose Escalation, First-in-human Clinical Trial to Evaluate the Safety, Pharmacokinetics and Preliminary Antitumor Activity of PEP-010, Administered as Single Agent and in Combination With Paclitaxel or With Gemcitabine in Patients With Metastatic Solid Cancer

Sponsor will share de-identified data sets documents generated under the project will be disseminated in accordance with Institut Curie policies.

The DLT is defined as any clinically significant non-hematological toxicity ≥ grade 3 and any hematological toxicity ≥ grade 4 of treatment-related adverse event

the ORR (objective response rate), defined as the proportion of patients who have achieved a complete response (CR) or partial response (PR) within the first 6 months

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of Intra-Arterial and Intra-Tumoral Ad-p53 With Capecitabine (Xeloda) or Anti-PD-1 in Liver Metastases of Solid Tumors and Recurrent Head and Neck Squamous Cell Cancer	NCT02842125	Metastatic Soli... Recurrent Head ...	Ad-P53 Xeloda Keytruda Opdivo	18 Years -	MultiVir, Inc.
First-in-human Phase I to Evaluate PEP-010 as Single Agent and in Combination With Paclitaxel or With Gemcitabine (CleverPeptide)	NCT04733027	Metastatic Soli...	Dose escalation...	18 Years -	Institut Curie
Safety and Efficacy of Intra-Arterial and Intra-Tumoral Ad-p53 With Capecitabine (Xeloda) or Anti-PD-1 in Liver Metastases of Solid Tumors and Recurrent Head and Neck Squamous Cell Cancer	NCT02842125	Metastatic Soli... Recurrent Head ...	Ad-P53 Xeloda Keytruda Opdivo	18 Years -	MultiVir, Inc.

Spots Global Cancer Trial Database for metastatic solid tumor cancer