Study to Evaluate the Safety and Efficacy of Treatment With NLM-001 and Standard Chemotherapy Plus Zalifrelimab in Patients With Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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In order to improve the survival rates and decrease progression of pancreatic advanced cancer, this study aims to evaluate the first line treatment approved for this disease (gemcitabine plus nab-paclitaxel) in combination with two experimental drugs, an inhibitor of the signaling pathway of Hedgehog and an immunotherapy drug able of blocking the CTLA-4 receptor.

Detailed Description
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Pancreatic cancer is one of the leading neoplasms in the world in terms of mortality, with very low survival rates mainly due to its rapid progression and diagnosis in advanced stages, which makes its treatment extremely difficult. Gemcitabine plus nab-paclitaxel is currently considered the first-line standard treatment for advanced pancreatic cancer due to this superiority against other treatments. In order to find an alternative to improve survival of advanced pancreatic cancer, this study aims to evaluate the efficacy with first-line treatment in combination of two experimental drugs, a Hedgehog pathway inhibitor (NLM-001) and a CTLA-4 blocker (zalifrelimab) in previously untreated patients with advanced pancreatic cancer.

Official Title
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Phase Ib/IIa Study to Evaluate Safety and Efficacy of Treatment With the Hedgehog Inhibitor NLM-001 and Chemotherapy (Gemcitabine and Nab-Paclitaxel) Plus Zalifrelimab as First Line Treatment in Patients With Advanced Pancreatic Cancer

Conditions
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Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Nab paclitaxel
* Drug: NLM-001
* Drug: Zalifrelimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Investigators must ensure that patients are able to understand the requirements of the study and provide informed consent Age ≥18 years Histological or cytological diagnosis of pancreatic adenocarcinoma Stage IV disease No prior treatment for advanced disease. Patients who have received chemotherapy for localize disease are eligible if at least six months have elapsed from the last chemotherapy treatment Measurable disease per RECIST 1.1 as determined by the investigator ECOG (Eastern Cooperative Oncology Group) PS 0-1 Sufficient hematopoietic, renal and liver function as defined as: Neutrophil count ≥ 1.5 x 10*9 / L Platelet count ≥ 100 x 10*9 / L Bilirubin ≤ 1.5 x ULN (upper limit of normal) AST and / or ALT ≤2.5 x ULN or ≤5 for patients with liver disease Serum creatinine ≤ 1.5 x ULN Tumor lesion amenable for safe repeated biopsy Women of child-bearing age and men who wish to participate in the study must agree to use appropriate contraceptive methods from the signing of informed consent until 3 months after discontinuation of the study drug Adequate contraception includes abstinence, oral contraceptives, transdermal patches, and injections that prolong release of a progestogen (starting at least 4 weeks prior to the administration of the investigational drug), double barrier method: condom or female condom (diaphragm or condom / vaginal) plus spermicide, intrauterine device (IUD), implant or a vaginal ring (placed at least 4 weeks prior to administration of investigational drug) or male partner sterilization (vasectomy with documentation of azoospermia) before the inclusion of the woman in the trial if the male is the only sex partner of the woman Investigators must ensure that patients recruited will be able to meet all study requirements, including tumor biopsy, chemotherapy and monitoring Exclusion Criteria: Active or uncontrolled infection, disease or serious medical condition that may interfere with the patient's eligibility or treatment History of psychiatric condition that would compromise the patient's ability to understand or comply with the requirements of the protocol, or the ability to provide informed consent Concurrent antineoplastic therapy Pregnant or lactating women History of allergic reactions attributed to compounds of similar chemical structure or similar biological study drug composition History of life-threatening serious adverse events to Gemcitabine or Nab-Paclitaxel Prior chemotherapy or chemo-radiation therapy for advanced pancreatic cancer Patients requiring or being treated with potent CYP3A4 inhibitors and inducers Other malignancies treated within the last 5 years, except in situ cervix carcinoma or nonmelanoma skin cancer History of interstitial lung disease Subjects with a history or presence of a known clotting disorder or difficulty achieving haemostasis will be excluded Primary or secondary immunodeficiency, including immunosuppressive disease or autoimmune disease (including autoimmune endocrinopathies). Note: Subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible. Subjects with Type 2 diabetes mellitus are allowed Subjects with a known history of human immunodeficiency virus 1 and 2, human T lymphotropic virus 1. Administration of anticancer medications or investigational drugs within the following intervals before the first administration of study drug: A 1-week washout is permitted for palliative radiation to non- central nervous system (CNS) disease, with medical monitor approval. Subjects must also not have had radiation pneumonitis as a result of treatment and cannot participate in the study if they are on chronic corticosteroids for radiation pneumonitis Note: Bisphosphonates and denosumab are permitted medications ≤7 days for prior corticosteroid treatment, with the following exceptions: Use of an inhaled or topical corticosteroid is permitted Corticosteroid premedication for radiographic imaging for dye allergies is permitted Use of physiologic corticosteroid replacement therapy may be approved after consultation with the medical monitor ≤7 days for immunosuppressive-based treatment for any reason, with the exceptions noted above for prior corticosteroid treatment ≤21 days or 5 half-lives before first dose of study treatment for all other investigational study drugs or devices. For investigational agents with long half-lives (e.g., >5 days), enrollment before the fifth half-life requires medical monitor approval Has not recovered to grade ≤1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting therapy Note: Subjects with grade ≤2 neuropathy and alopecia are an exception and may enroll History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful Concurrent participation in other investigational drug trials Known central nervous system (CNS) involvement as follows: Untreated CNS metastases. Leptomeningeal metastases. Note: Patients may be eligible if CNS metastases have been treated and patients have neurologically returned to baseline (except for residual signs and symptoms related to the CNS treatment).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational treatment<br>Conventional Chemotherapy (Gemcitabine + nab-paclitaxel) plus NLM-001 plus Zalifrelimab | Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2 IV on days 1, 8 and 15 (conventional chemotherapy).<br>Drug: Nab paclitaxel<br>* Nab-Paclitaxel 125 mg/m2 IV on days 1, 8 and 15 (conventional chemotherapy).<br>Drug: NLM-001<br>* NLM-001 will be administered three cycles consecutively followed by two rest cycles.<br>Drug: Zalifrelimab<br>* Zalifrelimab administration each 6 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment efficacy according to response | Objective Response Rate (ORR): Complete Response (CR) + Partial Response (PR) according to RECIST 1.1 criteria | 17 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of occurrence of adverse events | Frequency of occurrence of adverse events according to NCI-CTCAE v5.0 criteria | 8 months | 
| Treatment efficacy according to disease control rate | Disease Control Rate (DCR): Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) evaluated by RECIST 1.1 criteria | 8 months | 
| Treatment efficacy according to progression free survival (PFS) | Time in months from the patient's study enrolment until patient progression according to RECIST 1.1 criteria or death. | 8 months | 
| Treatment efficacy according to Duration of Response (DoR) | Time between the date of first confirmed response to the date of the first documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs first | 8 months | 
| Treatment efficacy according to Overall Survival (OS) | Time in months since the patient's study enrolment until death. | 8 months | 
| CA 19.9 | Decrease in CA 19.9 levels > 50% | 8 months | 
| Gli mRNA and SMA + CAF expression and ORR | Correlation between change in Gli mRNA and SMA + CAF expression and Objective Response Rate (ORR). | 1 month | 
| Gli mRNA and SMA + CAF expression and PFS | Correlation between change in Gli mRNA and SMA + CAF expression and Progression Free Survival (PFS). | 1 month | 
| Collagen structure and ORR | Correlation between change in Collagen structure and Objective Response Rate (ORR) | 1 month | 
| Collagen structure and PFS | Correlation between change in Collagen structure and Progression Free Survival (PFS). | 1 month | 
| Lymphocyte infiltration and ORR | Correlation between change in lymphocyte infiltration and Objective Response Rate (ORR). | 1 month | 
| Lymphocyte infiltration and PFS | Correlation between change in lymphocyte infiltration and Progression Free Survival (PFS). | 1 month |