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

• ClinicalTrials.gov Identifier: NCT01182246
• Recruitment Status: Unknown
• First Posted: August 16, 2010
• Last Update Posted: April 23, 2014
• Sponsor: Axcentua Pharmaceuticals AB
• Information provided by (Responsible Party): Axcentua Pharmaceuticals AB

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Adenocarcinoma	Drug: AXP107-11	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 44 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: November 2010
• Estimated Primary Completion Date: March 2016
• Estimated Study Completion Date: March 2016

Arms and Interventions

Arm

Intervention/treatment

Experimental: AXP107-11

Drug: AXP107-11; 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.; Other Name: genistein

Outcome Measures

Primary Outcome Measures :

1. Determine the safety profile and the maximum tolerated dose (MTD) of AXP107-11 alone and when given in combination with gemcitabine standard therapy. [ Time Frame: up to 6 months ]
   Safety (AEs, dose limiting toxicity, laboratory tests, vital signs, weight and ECG). MTD is defined at day 8.
2. 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). [ Time Frame: up to 6 months ]
   The tumour response evaluation will be performed according to RECIST (www.recist.org)

Secondary Outcome Measures :

1. To determine the pharmacokinetic (PK) profile of escalating doses of AXP107-11. [ Time Frame: Day -13, 1, 8 and 15 ]
   Plasma concentration of AXP107-11
2. To assess the safety and tolerability of a combination therapy of AXP107-11 and gemcitabine. [ Time Frame: up to 6 months ]

   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.

3. To assess the effect of a combination therapy of AXP107-11 and gemcitabine on overall survival (OS). [ Time Frame: up to 6 months ]
4. 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. [ Time Frame: up to 6 months ]
5. To assess the effect of a combination therapy of AXP107-11 and gemcitabine on time to progression (TTP). [ Time Frame: up to 6 months ]
6. 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). [ Time Frame: up to 6 months ]
   The tumour response evaluation will be performed according to RECIST (www.recist.org)
7. 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. [ Time Frame: up to 6 months ]
8. 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). [ Time Frame: up to 6 months ]
   Will be performed on the first 5 patients in the phase IIa part of the study.
9. 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). [ Time Frame: up to 6 months ]
10. 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. [ Time Frame: up to 6 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Sweden

Dept. of Clinical Science, Intervention and Technology, Div. of surgery, Karolinska University Hospital, Huddinge; Recruiting

Stockholm, Sweden, SE-141 86

Contact: Matthias Löhr +46 8 585 89591 matthias.loehr@ki.se

Principal Investigator: Mattias Löhr, MD, PhD,Prof.

Dept. of Oncology-Pathology, Karolinska University Hospital, Solna; Recruiting

Stockholm, Sweden, SE-17176

Contact: Jan-Erik Frödin +46 8 517 733 89 jan-erik.frodin@karolinksa.se

Principal Investigator: Jan-Erik Frödin, MD

Sponsors and Collaborators

Axcentua Pharmaceuticals AB

Investigators

• Principal Investigator: Mattias Löhr, MD,PhD, Prof.; Karolinska Institutet

More Information

• Responsible Party: Axcentua Pharmaceuticals AB
• ClinicalTrials.gov Identifier: NCT01182246
• Other Study ID Numbers: AXP-CT-001
• First Posted: August 16, 2010
• Last Update Posted: April 23, 2014
• Last Verified: April 2014

Keywords provided by Axcentua Pharmaceuticals AB:

adenocarcinoma; Pancreatic cancer

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Genistein; Anticarcinogenic Agents; Protective Agents; Physiological Effects of Drugs; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Phytoestrogens; Estrogens, Non-Steroidal; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists