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

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

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.

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.

Inclusion Criteria:

1. Age ≥ 18 years at the time of signing the informed consent
2. Histologically confirmed adenocarcinoma of the pancreas
3. Metastatic or locally advanced, unresectable disease stage III-IV.
4. Measurable disease according to the international criteria proposed by the Response Evaluation Criteria in Solid tumors (RECIST) for target lesions
5. Karnofsky Performance Status ≥ 70 at study entry (Appendix 18.4).
6. Life expectancy of more than three months
7. Negative pregnancy test for female patients
8. For fertile women, willingness to perform double-barrier contraception during study and for four weeks after last treatment
9. Able and willing to sign the informed consent form

Exclusion Criteria:

1. Previous or ongoing severe supraventricular or ventricular arrhythmia

2. Previous or ongoing coagulation or bleeding disorder (PTT > 1.5 x ULN)

3. HIV infection

4. Known hypersensitivity to any component of the AXP107-11 formulation or gemcitabine

5. Previous or ongoing significant liver pathology (other than metastases) and/or liver function disorders

6. Previous or ongoing significant chronic renal dysfunction

7. Previous or ongoing malignancy other than pancreatic cancer < five years prior to enrolment, except basal cell carcinoma treated locally

8. Cardiovascular disease, New York Heart Association (NYHA) classification III or IV16

9. Severe pulmonary obstructive or restrictive disease

10. Acute or chronic inflammation (autoimmune or infectious)

11. Significant active/unstable non-malignant disease likely to interfere with study assessments

12. 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

13. Immunotherapy within six weeks prior to enrolment.

14. Any chemotherapeutical treatment for pancreatic adenocarcinoma before enrolment

15. Any radiotherapy for pancreatic adenocarcinoma before enrolment except for treatment of bone metastases if target lesions are not included in the irradiated field

16. Major surgery within four weeks prior to enrolment

17. Pregnant or nursing woman

18. Participations in other interventional clinical study within four weeks of enrolment