Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Rare Diseases

Pancreatic Neoplasms

Influenza, Human

Communicable Diseases

Respiratory Tract Infections

Orthomyxoviridae Infections

Virus Diseases

RNA Virus Infections

Respiratory Tract Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Vaccines

Immunomodulating Agents

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

SBRT of 15 Gy will be given on day 1 of the first cycle. Nivolumab 3 mg/kg (up to 240 mg maximum) will be given on day 1 (± 3 days) of each 14-day treatment cycle until the progression of disease or maximum of 48 weeks, discontinuation due to toxicity, withdrawal of consent. Ipilimumab 1 mg/kg will be given on day 1 cycle 1 (± 3 days) and once more after 6 weeks. Nivolumab will be administered as an IV infusion over 60 (± 5) minutes and then, after a 30 minutes rest period, ipilimumab will be administered as an IV infusion over 30 (± 5) minutes. Seasonal influenza vaccine is given IM or via PharmaJet Stratis Needle-Free Injection System, 0.5 mL per dose as a single on day 1 cycle 1 (± 3 days).

3 mg/kg (up to 240 mg maximum) will be given on day 1 (± 3 days) of each 14-day treatment cycle

1 mg/kg will be given on day 1 cycle 1 (± 3 days) and once more after 6 weeks

Seasonal influenza vaccine is given IM or via PharmaJet Stratis Needle-Free Injection System, 0.5 mL per dose as a single on day 1 cycle 1 (± 3 days)

Influenza vaccine

* A total dose of 15 Gy as a single fraction is prescribed as the mean dose to the PTV.
* PTV should be covered by 95% isodose (PTV D99% \> 95%).

SBRT

Inna M Chen

Pancreatic cancer (PC) remains a dreadful disease due to its often advanced stage at diagnosis and poor sensitivity to chemotherapy. Progression after 1. line chemotherapy is inevitable in patients with advanced PC, and treatment options for patients who progress after 1. line chemotherapy are limited. Considering the emerging role of the tumor microenvironment, the combination of checkpoint blocking antibodies with immunomodulation of the tumor microenvironment could lead to better responses in tumor historically resistant to radiation and checkpoint blocking antibody approaches as single modalities. Influenza vaccination in cancer patients receiving immune checkpoint inhibitors resulted in a better survival, irrespective of the anticancer treatment outcome. Influenza vaccine facilitates both T- and B cell activation and drives interferon-gamma response, supporting the rationale for combining of influenza vaccine with immune checkpoint inhibition and radiation (NCT02866383).

Based on these considerations, the proposed treatment with SBRT of 15 Gy in combination with nivolumab, ipilimumab and influenza vaccine may have the potential to provide meaningful clinical benefit by generating durable clinical responses, thereby improving quality of life (QoL) and potentially extending survival.

Pancreatic cancer (PC) is the fourth leading cause of cancer death, and each year 1000 Danes are diagnosed with PC, 80% of which are advanced stage. Survival rates are meager, currently approaching 10% at 5 years postdiagnosis, and have scarcely improved over the last 50 years. PC is highly resistant to conventional treatments, and nearly all patients develop metastases and die. As the incidence of PC continuously rises while treatment response rates remain incredibly low, a lack of effective therapy options and accurate predictive biomarkers is a real cause for concern and underlines the need for further research in this area.

Immunotherapy has not been successful in PC patients primarily due to a lack of pre-existing T-cell immunity and/or a highly immunosuppressive tumor microenvironment. "Non-immunogenicity" of PC with high prevalence of immunosuppressive cells and typically a scarcity of tumor-infiltrating effector lymphocytes is considered as one of the reasons for lacking responsiveness to single-agent immunotherapies. Considering the emerging role of the tumor microenvironment, the combination of checkpoint blocking antibodies with immunomodulation of the tumor microenvironment could lead to better responses in tumor historically resistant to radiation and checkpoint blocking antibody approaches as single modalities. Preliminary data from the phase 2 study CHECKPAC (NCT02866383) showed durable clinical benefit in a small subgroup of patients after the addition of stereotactic body radiation therapy (SBRT) of 15 Gy to the combination of nivolumab and ipilimumab (Herlev internal data) in patients with resistant metastatic PC.

Influenza vaccination in cancer patients receiving immune checkpoint inhibitors inexplicably was associated with a better survival, irrespective of the anticancer treatment outcome. Influenza vaccine facilitates both T- and B cell activation and drives interferon-gamma response, supporting the rationale for combining of influenza vaccine with CHECKPAC strategy. Based on these considerations, the proposed treatment with nivolumab, ipilimumab and radiation in combination with influenza vaccine may potentially provide meaningful clinical benefit by generating durable clinical responses, thereby improving quality of life (QoL) and potentially extending survival.

Subjects will be enrolled in the study to treatment with nivolumab, ipilimumab and radiation in combination with influenza vaccine, until 30 participants have been treated.

Immunotherapy Combined With Radiation and Influenza Vaccine for Pancreatic Cancer.

Nivolumab, Ipilimumab and Radiation in Combination With Influenza Vaccine in Patients With Pancreatic Cancer (INFLUENCE)

ORR in all patients using Investigator assessments

DoR in all patients using Investigator assessments according to RECIST 1.1.

DCR in all patients using Investigator assessments according to RECIST 1.1.

PFS in all patients using Investigator assessments according to RECIST 1.1.

OS in all patients using Investigator assessments according to RECIST 1.1.

Adjusted mean change from baseline in global QoL

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Herlev Hospital

Principal Investigator

Recurrence

Antibodies

Durvalumab

Immunoglobulins

Mitogens

(Dose Escalation and Cohort Expansion) Galunisertib administered orally in combination with durvalumab administered intravenously (IV).

Galunisertib

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

The main purpose of this study is to evaluate the safety and efficacy of the study drug known as galunisertib administered in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody durvalumab in participants with refractory metastatic pancreatic cancer.

A Study of Galunisertib (LY2157299) and Durvalumab (MEDI4736) in Participants With Metastatic Pancreatic Cancer

A Phase 1b Dose-Escalation and Cohort-Expansion Study of the Safety, Tolerability, and Efficacy of a Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor (Galunisertib) Administered in Combination With the Anti-PD-L1 Antibody Durvalumab (MEDI4736) in Recurrent or Refractory Metastatic Pancreatic Cancer

AstraZeneca

Eli Lilly and Company

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Endometrial Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Antibodies, Monoclonal

Paclitaxel

Carboplatin

Pembrolizumab

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Standard Chemotherapy will be adminitred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Experimental double combination \[Standard Chemotherapy +NP137\] will be administred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Experimental double combination \[Pembrolizumab +NP137\] will be administred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Experimental triple combination \[Pembrolizumab+ Standard Chemotherapy + NP137\] will be administred in 2 independant cohorts: Endometrial carcinoma or Cervix Carcinoma

Recombinant humanized IgG1 monoclonal antibody against Netrin 1. NP137 will be administred IV, Q3W until disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, pregnancy or SMPC guidance, whichever occurs first.

NP137

Humanised monoclonal anti-programmed cell death-1 (PD-1) antibody will be administred in IV Q3W. A maximum 35 cycles of treatments (approximately 2 years) with pembrolizumab can be administered to patients.

Standard Chemotherapy agent will be administred IV, Q3W, up to 6 cycles of treatment.

Ray-Coquard Isabelle, MD, PhD

Elsa KALBACHER, MD

Coriolan LEBRETON, MD

Florence JOLY, MD

Jean-David FUMET, MD

Cyril ABDEDDAIM, MD

Isabelle RAY COQUARD, MD,PhD

Magali PROVANSAL, MD

Michel FABBRO, MD

Jean-Sébastien FRENEL, MD

Frederic SELLE, MD

Alexandre DE MOURA, MD

Alexandra LEARY, MD

Jerome ALEXANDRE, MD, PhD

Thibault DE LA MOTTE ROUGE, MD

Laurence GLADIEFF, MD

The aim of this study is to investigate the safety and the clinical activities of NP137 when combined with pembrolizumab and/or chemotherapies in patients with advanced/metastatic gynecological cancers (2 types: endometrial carcinoma and cervix carcinoma).

The prognosis of patients with locally advanced/metastatic uterine (endometrial or cervical) cancer progressing/relapsing after at least one prior systemic treatment remains poor. The development of new innovative anti-tumor drug candidates as single agent or in combination with chemotherapy or check point inhibitors is needed.

NP137 is a first-in-class humanized monoclonal antibody targeting specifically and selectively Netrin-1. By blocking Netrin-1, NP137 is capable of restoring apoptosis in tumor cells in vitro and in vivo, leading to therapeutic activity in various animal cancer models.

Dependence receptors inhibitor such as NP137 might be a novel choice to improve the clinical outcomes of these patients.

The herein proposed study will be a multicenter, open-label, randomized, Phase I/II trial with:

A safety run in part to assess the safety of the therapeutic combinations for the first 6 patients enrolled in each of the therapeutic combinations independently of the tumor type. According to safety rules, these therapeutic combinations will be investigated or not in the Phase II part.

A Phase II part will be then conducted using an adaptive Bayesian approach allowing to quickly stop treatment cohorts without evidence of efficacy and/or select promising treatment cohorts. The Phase II part will be initiated with a preliminary step to assess the clinical activity of the proposed therapeutic combinations in 2 tumor types before proceeding to the activation of extension phase II part of the study. For each cohorts, clinical activity will be assessed through by sequential statistical analysis at specific timepoints.

GYNecological Cancers Treated With NETrin mAbs in Combination With Chemotherapy and /or Pembrolizumab

A Randomized, Multicenter, Open Label, Phase I/II Study to Evaluate the Safety, Clinical and Biological Activity of a Humanized Monoclonal Antibody Targeting Netrin-1 (NP137) in Combination With Carboplatin Plus Paclitaxel and/or Pembrolizumab in Patients With Locally Advanced/Metastatic Endometrial Carcinoma or Cervix Carcinoma Progressing/Relapsing After at Least One Prior Systemic Chemotherapy.

Any pre-definied toxicities graded by using NCI CTCAE Version 5.0 and assessed by the investigator to be possibly, probably, or definitely related to study treatments administration during the safety run in period

Rate of patients with CR or PR as per RECIST 1.1

The proportion of evaluable patients with an objective response according to RECIST 1.1.

Time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression or death is documented,

Time from first study drug intake until disease progression or death, whichever occurs first

Time from the first day of study treatment to the date of death due to any cause.

The best response designation between the date of the first study treatment and the date of objectively documented progression or the date of subsequent anti-cancer therapy

Area under the concentration-time curve from time zero to the last sample with the quantifiable concentration

Area under the concentration-time curve from time zero to infinity corresponding to the definite integral of a curve that describes the variation of a drug concentration in blood plasma as a function of time (drug exposure in plasma)

Clearance: volume of plasma from which NP137 is completely removed per unit time.

Terminal elimination half-life: time required for the amount of NP137 in the body to decrease by half.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy Combined With Radiation and Influenza Vaccine for Pancreatic Cancer.	NCT05116917	Pancreatic Canc...	Nivolumab Ipilimumab Influenza vacci... SBRT	18 Years -	Herlev Hospital
A Study of Galunisertib (LY2157299) and Durvalumab (MEDI4736) in Participants With Metastatic Pancreatic Cancer	NCT02734160	Metastatic Panc...	Galunisertib Durvalumab	18 Years -	Eli Lilly and Company
GYNecological Cancers Treated With NETrin mAbs in Combination With Chemotherapy and /or Pembrolizumab	NCT04652076	Endometrial Car... Cervix Carcinom...	NP137 Pembrolizumab Paclitaxel Carboplatin	18 Years -	NETRIS Pharma

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