AXP107-11 in Combination With Standard Gemcitabine (Gemzar® ) Therapy for Treatment in Patients With Pancreatic Cancer

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect and safety of AXP107-11 alone, and in combination with gemcitabine standard therapy, in patients with advanced or metastatic cancer of the pancreas. The safety, pharmacokinetics and efficacy of AXP107-11 in these patients will also be studied.

Detailed Description
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The annual incidence rate of pancreatic cancer is almost identical to the mortality rate. Despite a low incidence rate, pancreatic cancer is the fourth leading cause of cancer mortality in both men and women. Today is the only potentially curative option of these patients complete surgical resection. However, a majority of the patients (up to 80%) are not eligible for surgery for different reasons. Today is gemcitabine the accepted first-line treatment for these patients. Recent advances in the management of pancreatic cancer suggest that gemcitabine may be improved by combining it with other anticancer drugs. One attractive therapeutic option is genistein. Genistein appears to sensitize tumors to chemotherapy both by targeting the tumor cells and also by targeting components of the tumor microenvironment. However, the limited bioavailability of genistein in its known crystalline form has led to difficulties in attaining adequate plasma concentration, resulting in limited application and dissemination in the clinical setting. To overcome this limitation, a novel crystalline form of genistein with improved pharmaceutical properties is being used. AXP107-11, a crystalline salt of genistein has improved physiochemical properties (solubility, dissolution rate, bioavailability) as compared to the known crystalline form of genistein. In this study, AXP107-11, will be investigated alone and in combination with gemcitabine in patients with pancreatic cancer.

Official Title
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Safety, Pharmacokinetics and Efficacy of AXP107-11 in Combination With Standard Gemcitabine (Gemzar®) Treatment in Patients With Locally Advanced or Metastatic, Unresectable, Adenocarcinoma of the Pancreas, Stage III-IV: A Prospective, Open Label, Multi-centre, Sequential Phase Ib/IIa Study

Conditions
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Adenocarcinoma

Intervention / Treatment
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* Drug: AXP107-11


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at the time of signing the informed consent Histologically confirmed adenocarcinoma of the pancreas Metastatic or locally advanced, unresectable disease stage III-IV. Measurable disease according to the international criteria proposed by the Response Evaluation Criteria in Solid tumors (RECIST) for target lesions Karnofsky Performance Status ≥ 70 at study entry (Appendix 18.4). Life expectancy of more than three months Negative pregnancy test for female patients For fertile women, willingness to perform double-barrier contraception during study and for four weeks after last treatment Able and willing to sign the informed consent form Exclusion Criteria: Previous or ongoing severe supraventricular or ventricular arrhythmia Previous or ongoing coagulation or bleeding disorder (PTT > 1.5 x ULN) HIV infection Known hypersensitivity to any component of the AXP107-11 formulation or gemcitabine Previous or ongoing significant liver pathology (other than metastases) and/or liver function disorders Previous or ongoing significant chronic renal dysfunction Previous or ongoing malignancy other than pancreatic cancer < five years prior to enrolment, except basal cell carcinoma treated locally Cardiovascular disease, New York Heart Association (NYHA) classification III or IV16 Severe pulmonary obstructive or restrictive disease Acute or chronic inflammation (autoimmune or infectious) Significant active/unstable non-malignant disease likely to interfere with study assessments Laboratory tests (hematology, chemistry) outside specified limits: WBC ≤ 3 x 10³/mm³ ANC ≤ 1.5 x 10³/mm³ Platelets ≤ 100.000/mm³ Hb ≤ 9.0 g/dl (≤ 5.6 mmol/l) PT/PTT > 1.5 x ULN Serum creatinine > 130 μmol/l) or clearance < 60 ml/min AST and/or ALT > 3 x ULN with the exception of patients with liver metastasis (> 5 x ULN) Alkaline phosphatase > 3 x ULN Total bilirubin > 3 x ULN Immunotherapy within six weeks prior to enrolment. Any chemotherapeutical treatment for pancreatic adenocarcinoma before enrolment Any radiotherapy for pancreatic adenocarcinoma before enrolment except for treatment of bone metastases if target lesions are not included in the irradiated field Major surgery within four weeks prior to enrolment Pregnant or nursing woman Participations in other interventional clinical study within four weeks of enrolment

Ages Eligible for Study
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Minimum Age: 18 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: AXP107-11<br> | Drug: AXP107-11<br>* The drug substance, AXP107-11, is a crystalline form of genistein, a substance shown in literature data to target pancreatic tumor cells and also the tumor microenvironment and thus sensitizes tumors to chemotherapy. AXP107-11 is formulated in a capsule containing 2x100 mg of active substance. A maximum of four cohorts of three to six patients each will be treated with escalating dose levels of AXP107-11 alone (two weeks) and in combination with gemcitabine (one week). AXP107-11 capsules will be ingested orally twice daily (morning and evening) each day of the treatment period. In phase Ib, AXP107-11 will be administered once daily on the first treatment day (morning), followed by twice daily administrations continuously throughout the treatment period. When a minimum of six patients have been treated and evaluated on the maintenance dose (phase 1b), additional patients will be included directly into phase IIa.<br>* Other names: genistein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the safety profile and the maximum tolerated dose (MTD) of AXP107-11 alone and when given in combination with gemcitabine standard therapy. | Safety (AEs, dose limiting toxicity, laboratory tests, vital signs, weight and ECG). MTD is defined at day 8. | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on objective response rate defined as the percentage of patients who showed complete response (CR) or partial response (PR). | The tumour response evaluation will be performed according to RECIST (www.recist.org) | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the pharmacokinetic (PK) profile of escalating doses of AXP107-11. | Plasma concentration of AXP107-11 | Day -13, 1, 8 and 15 | 
| To assess the safety and tolerability of a combination therapy of AXP107-11 and gemcitabine. | Assessed by occurrence of adverse events, abnormal changes in laboratory parameters, vital signs, ECG, relevant patient withdrawal and percentage of patients having reduction, omission or discontinuation of any study medication. Note: This is a secondary outcome measurement for patients in the phase IIa part of the study. This is a primary objective in phase Ib. | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on overall survival (OS). |  | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on overall survival rate at six months after start of combination therapy. |  | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on time to progression (TTP). |  | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on palliation, defined as the percentage of patients who showed CR, PR or stable disease (SD). | The tumour response evaluation will be performed according to RECIST (www.recist.org) | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on clinical benefit response, a composite of measurements of pain (pain intensity and analgesics consumption), Karnofsky performance status and weight. |  | up to 6 months | 
| To assess the effect of combination therapy of AXP107-11 and gemcitabine on the tumor mass using F-18 fluorodeoxyglucose positron emission tomography (FDG-PET). | Will be performed on the first 5 patients in the phase IIa part of the study. | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on symptom distress score as measured by the Edmonton Symptom Assessment System (ESAS). |  | up to 6 months | 
| To assess the effect of a combination therapy of AXP107-11 and gemcitabine on quality of life as assessed by the EORTC QLQ-C30 questionnaire and the PAN26 module. |  | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma, Pancreatic cancer