Study of CG200745 PPA in Combination With Gemcitabine and Erlotinib for Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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<Part I - Phase I trial> The phase I clinical trial is to identify the MTD (Maximum Tolerated Dose) and DLT (Dose Limiting Toxicity) of CG200745 PPA in combination use of Gemcitabine and Erlotinib. Initial dose of CG200745 PPA is 187.5 mg/m^2, and it will be extended to 250 mg/m^2, 312.5 mg/m^2 or it will be reduced to 125 mg/m^2 based on the results of the cohort of 3 subjects per dose level. Based on the 3+3 dose escalation study design, Gemcitabine and Erlotinib are administered as fixed doses, whereas CG200745 PPA is to be administered as in four different cohorts according to the dose level. Each cohort consists of 3 or 6 subjects. <Part II - Phase II trial> In the phase II clinical trial, the subjects will be administered with the dose which is to be identified as a recommended dose based on the results of Phase I study. The whole one cycle is consisted of 28 days, same as the phase I. The entire treatment period is 6 cycles and tumor assessment is evaluated every 2 cycles.

Detailed Description
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<Part I - Phase I trial> The phase I clinical trial is to identify the MTD and DLT of CG200745 PPA in combination use of Gemcitabine and Erlotinib. Initial dose of CG200745 PPA is 187.5 mg/m^2, and it will be extended to 250 mg/m^2, 312.5 mg/m^2 or it will be reduced to 125 mg/m^2 based on the results of the cohort of 3 subjects per dose level. Based on the 3+3 dose escalation study design, Gemcitabine and Erlotinib are administered as fixed doses, whereas CG200745 PPA is to be administered as in four different cohorts according to the dose level. Each cohort consists of 3 or 6 subjects. Dose level 0: CG200745 PPA 125 mg/m^2 puls Gemcitabine 1000 mg/m^2) and Erlotinib 100 mg Dose level 1: CG200745 PPA 187.5 mg/m^2 puls Gemcitabine 1000 mg/m^2) and Erlotinib 100 mg Dose level 2: CG200745 PPA 250 mg/m^2 puls Gemcitabine 1000 mg/m^2) and Erlotinib 100 mg Dose level 3: CG200745 PPA 312.5 mg/m^2 puls Gemcitabine 1000 mg/m^2) and Erlotinib 100 mg <Part II - Phase II trial> In the phase II clinical trial, the subjects will be administered with the dose which is to be identified as a recommended dose based on the results of Phase I study. The whole one cycle is consisted of 28 days, same as the phase I. The entire treatment period is 6 cycles and tumor assessment is evaluated every 2 cycles.

Official Title
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A Phase I/II Study of Combination Therapy of CG200745 PPA With Gemcitabine and Erlotinib to Determine the Maximum Tolerated Dose (MTD) and Evaluate the Safety and Efficacy for Locally Advanced Unresectable, or Metastatic Pancreatic Cancer

Conditions
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Pancreatic Neoplasms

Intervention / Treatment
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* Drug: CG200745 PPA
* Drug: Gemcitabine
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages: ≥ 20 and ≤ 75 years Subjects who join voluntarily for participation in the study, sign the consent form and are willing to comply the clinical trial procedure Subjects who have diagnosed with unresectable, locally advanced, metastatic, histologically and cytologically confirmed pancreatic adenocarcinoma ECOG (Eastern Cooperative Oncology Group) performance status: 0-2 Estimated life expectancy at the time of enrollment is more than 3 months Adequate hematological, renal and hepatic function Absolute neutrophil count (ANC) ≥ 1500/mm3, hemoglobin ≥ 9.0 g/dl (eligible if hemoglobin lab values are adjusted with blood transfusion), platelet ≥ 100,000/mm3 Within normal range of serum creatinine or creatinine clearance rate (CCr) ≥ 60 ml/min (using Cockcroft-Gault equation ) Subjects who have no abnormal serum electrolyte values (including calcium, magnesium, phosphorous and potassium). However, the supplementation therapy is allowed for normalization of serum electrolytes. ※ Normal reference range for Calcium: 8.3 10.5 mg/dl, Magnesium: 1.58 3.0 mg/dl, Phosphorous: 2.4 4.5 mg/dl, Potassium: 3.3 5.5 mmol/L Serum bilirubin < 2 x Upper Limit Normal (ULN), Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) < 2.5 x ULN, Alkaline phosphatase (ALP) < 5 x ULN (If liver metastasis, AST/ALT <5 x ULN) Prothrombin Time (PT) or Partial thromboplastin time (PTT) ≤ 1.5 x ULN (except for the use of anticoagulant, in this case, PT/PTT stabilization for up to 2 weeks should be confirmed) No prior chemotherapy, radiation or biologics Exclusion Criteria: Subject who had experienced a major surgery within 2 weeks prior to the screening visit Subject with an evidence for uncontrolled brain metastasis (except for the patients with radiologically and neurologically stable brain metastasis without corticosteroid therapy for at least two weeks) Subject who cannot be administered oral drug, or have difficulty to absorb the study drugs due to a history of major gastrointestinal surgery or pathological findings. Subjects who have treated antibiotics within last seven days due to an active bacterial infection prior to the enrollment. (Topical antibiotic therapies are excluded) Subjects who had experienced any malignancies within past 5 years, except for basal cell skin cancer, in situ cervical cancer, or papillary thyroid tumor. Pregnancy or Lactating Fertile subjects who do not agree with the effective contraception during the study period and up to 3 months after the completion of the study. The following cases are exceptions: an irreversible and surgical sterility by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, and menopausal women over 50 years old with no menstruation for at least 12 months and without hormonal therapy. Tubal ligation is not regarded as an effective contraception Subject who cannot take anti-cancer chemotherapy due to a systemic disease (ex. chronic renal failure) Subjects who have treated with any other investigational drug within 4 weeks prior to the screening visit History of hypersensitivity to study drug Subject with HIV positive

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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: CG200745 PPA<br>CG200745 PPA plus Gemcitabine and Erlotinib | Drug: CG200745 PPA<br>* CG200745 PPA IV every week three times per cycle (4 weeks)<br>* Other names: CG200745 PPA (phosphoric acid);Drug: Gemcitabine<br>* 1000 mg/m^2 intravenously every week three times per cycle (4 weeks)<br>* Other names: combination therapy 1;Drug: Erlotinib<br>* 100 mg per oral daily per cycle (4 weeks)<br>* Other names: combination therapy 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is the proportion of the subjects with CR and PR in comparison to the total subjects at the final tumor assessment point (cycle 6) from the baseline | up to 6 cycles (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) | DCR is the proportion of the subjects with Complete Response (CR), Partial Response (PR), and stable disease (SD) in comparison to the total subjects at the final tumor assessment point (cycle 6) from the baseline | up to 6 cycles (each cycle is 28 days) | 
| Area Under the Curve [AUC] | Pharmacokinetics (PK) parameter | before the administration and up to 1440 mins after completion of the IP (Investigational Product) administration | 
| Maximum Plasma Concentration [Cmax] | Pharmacokinetics (PK) parameter | before the administration and up to 1440 mins after completion of the IP administration | 
| Adverse Events | safety parameter | up to 6 cycles (each cycle is 28 days) | 
| Clinical laboratory tests | safety parameter | up to 6 cycles (each cycle is 28 days) |