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Title A 3-Arm Phase 2 Double-Blind Randomized Study of Gemcitabine, Abraxane® Plus Placebo versus GemcitabIne, Abraxane® plus 1 or 2 Truncated Courses of Demcizumab in Subjects with 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma

IRB OMP1215

CC 15-820

Hospital Main Campus

Phase Phase 2

Disease Pancreas

Drug Abraxane , Demcizumab , Gemcitabine

Description

Primary Objective:

• To compare the efficacy of Arm 1 to the pooled decizumab arms (i.e., Arm 1 to Arms 2 and 3) (See Section 5.0 for description of Treatment Arms) in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma

Secondary Objectives:

• To compare the efficacy of Arm 1 to Arm 2 and Arm 1 to Arm 3 in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma
• To compare the safety of Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
• To determine the rate of immunogenicity against demcizumab when combined with Abraxane® and gemcitabine in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
• To determine population pharmacokinetics of demcizumab in subjects receiving demcizumab and Abraxane® and gemcitabine in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.

Exploratory Objectives:

• To compare the safety and efficacy of Arm 2 to Arm 3 in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
• To compare the exploratory biomarkers of Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.

Inclusion Criteria

1. Subjects must have cytologically or histologically confirmed metastatic pancreatic ductal adenocarcinoma. Prior chemotherapy and/or radiotherapy either in the adjuvant or neoadjuvant setting or for metastatic disease is not allowed.
2. Age ≥ 21 years
3. ECOG performance status 0 or 1 (see Appendix C)
4. Measurable disease per RECIST v1.1 (Appendix D)
5. Adequate organ and marrow function as defined below:
   • Absolute neutrophil count ≥1.5 x 10⁹/L without granulocyte colony-stimulating factor support within 2 weeks prior to randomization
   • Hemoglobin ≥100 g/L without transfusion within 2 weeks prior to randomization
   • Platelets ≥125 X 10⁹/L without transfusion within 2 weeks prior to randomization
   • Total bilirubin ≤1 X institutional upper limit of normal (ULN)
   • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤5 X institutional ULN
   • Alkaline phosphatase ≤5 X institutional ULN
   • Albumin ≥ 3 g/dL
   • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) within 1.5 X the institutional ULN
   • Creatinine ≤1.5 X institutional ULN OR
   • Calculated creatinine clearance ≥60 mL/min using the Cockcroft and Gault formula as follows: Creatinine clearance (mL/min) = (140 - age) x ideal body weight [kg] 0.814 x serum creatinine [μmol/L]. For women, multiply the value from the equation above by 0.85. Where age is in years, weight is in kg, and serum creatinine is in μmol/L. The ideal body weight for use in the Cockcroft and Gault formula should be determined as follows: Men: 50 + [(Height (cm) -154) X 0.9]; Women: 45.5 + [(Height (cm) -154) X 0.9].
6. For women of childbearing potential and men with partners of childbearing potential, agreement (by subject and/or partner) to use two effective forms of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) from study entry through at least 6 months after the termination visit.
   • Women of childbearing potential are those women who have not been permanently sterilized or are not postmenopausal. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.
   • Highly effective methods of birth control include those that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, levonorgestrel-releasing intrauterine system, intra-uterine devices (IUDs), vasectomized partner, and true sexual abstinence.
7. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

1. Subjects with a neuroendocrine tumor of the pancreas, an acinar tumor of the pancreas or a pancreatic tumor with mixed histologies.
2. Subjects receiving any other investigational medicinal products or anti-cancer therapy.
3. Subjects with brain metastases (subjects must have a CT scan or MRI of the head within 28 days prior to randomization to rule out brain metastases), uncontrolled seizure disorder, or active neurologic disease
4. Subjects with leptomeningeal disease
5. Subjects with ≥ Grade 2 peripheral neuropathy
6. History of interstitial pulmonary disease or pneumonitis
7. Malignancies other than pancreatic cancer successfully treated within 3 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, treated superficial bladder cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent
8. Prior radiation to the chest wall or mediastinum if the radiation field involves the heart
9. History of a significant allergic reaction attributed to humanized or human monoclonal antibody therapy
10. Significant intercurrent illness that will limit the patient�s ability to participate in the study or may result in their death over the next 18 months.
11. Pregnant women or nursing women
12. Subjects with known HIV infection
13. Known bleeding disorder or coagulopathy
14. Subjects receiving therapeutic doses of heparin, warfarin, factor Xa inhibitors or other similar anticoagulants. Note: Subjects may be receiving prophylactic doses of heparin, warfarin, factor Xa inhibitors or other similar anticoagulants, low-dose aspirin and/or non-steroidal anti-inflammatory agents.
15. Subjects with known clinically significant gastrointestinal disease including, but not limited to, inflammatory bowel disease
16. Subjects with a blood pressure of ≥140/90 mmHg. The BP should be taken using the method described in Section 9.3. Subjects taking antihypertensive medications must be taking ≤ 2 medications to obtain this level of BP control.
17. Subjects with tumors that are currently involving the lumen of the gastrointestinal tract
18. History of cerebral vascular accident (CVA) or transient ischemic attacks (TIAs) within 6 months prior to randomization, major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipation of need for major surgical procedure during the course of the study. Placement of vascular access device will not be considered major surgery.
19. Subjects with an active infection requiring antibiotics
20. Subjects with an uncontrolled seizure disorder or active neurologic disease
21. Any of the following cardiac-related criteria:
    • B-type natriuretic peptide (BNP) value of ≥100 pg/mL
    • Left ventricular ejection fraction (LVEF) ≤50%
    • Peak tricuspid velocity ≥3.0 m/s on Doppler echocardiogram
    • Receiving any medications for cardiac ischemia
    • Current evidence of cardiac ischemia
    • History of acute myocardial infarction within 6 months prior to randomization
    • New York Heart Association Classification II, III, or IV (See Appendix E) For subjects to meet class II criteria with mild shortness of breath and/or angina, as defined by the NYHA guidelines, the cardiac etiology of the symptoms should be confirmed by a cardiologist taking 12-lead electrocardiogram, transthoracic Doppler echocardiogram and other studies into consideration, as appropriate.
    • History of heart failure or pulmonary hypertension
    • Received a total cumulative dose of ≥ 400 mg/m² doxorubicin
    • Grade ≤ 2 ventricular arrhythmia
    • Inability to comply with study and follow-up procedures