RAmucirumab Combined wIth Standard Nab-paclitaxel and Gemcitabine as First-line Chemotherapy in Patients With Advanced Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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RACING (RAmucirumab Combined wIth standard Nab-paclitaxel and Gemcitabine as first-line chemotherapy in patients with advanced pancreatic adenocarcinoma) trial is a Greek, investigator-initiated, single-arm, open-label phase Ib-II study. Patients with advanced cytologically or histologically proven pancreatic adenocarcinoma will be treated with a combination of Ramucirumab with Nab-paclitaxel and Gemcitabine (for a maximum of 8 cycles followed by Ramucirumab maintenance) until disease progression or excessive Adverse Events (AEs) or Investigator's decision or patient's refusal of further treatment or death, whichever comes first.

Detailed Description
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Phase Ib: The first 12 patients will enter the phase Ib study in 2 cohorts of 6 patients each. In the first cohort, six patients will start Ramucirumab followed by Nab-paclitaxel and Gemcitabine every 4 weeks for 2 cycles at the specific initial dose level.When the dose is determined in the first cohort, then the second cohort will be enrolled to test the safety of this dose. The Phase II Recommended dose (RD) for the phase II part of the study will be determined when all 6+6 patients will complete a maximum of 2 cycles. Phase II: In the phase II part of the trial, new patients will be recruited and start the study treatment according to the RD determined at the second cohort of the phase Ib part. Phase Ib patients will enter the phase II part by continuing the treatment beyond the second cycle at the RD level. All the patients will continue the treatment until disease progression or excessive AEs or completion of 8 cycles of Nab-paclitaxel/Gemcitabine/Ramucirumab. In patients with no progressive disease, ramucirumab monotherapy will be administered after the completion of 8 cycles of chemotherapy. The primary endpoint will be Objective Response Rate (ORR) by RECIST criteria. Secondary endpoints will be Safety, Progression-free survival (PFS) and Overall Survival (OS). All the phase II endpoints will be assessed during BOTH the phase Ib and the phase II parts of the study. Patients enrolled at the phase Ib part will start being assessed for efficacy endpoints (response rate, PFS, OS) from the first date of registration to the study and will continue being assessed for efficacy also after passing to the phase II part of the study in a seamless way. After completion of patient enrollment in the phase Ib part, new patients will be enrolled directly to the phase II part. These patients will start being assessed for efficacy endpoints again from the first day of registration to the study.

Official Title
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Phase Ib-II Study of Ramucirumab Combined With Standard Nab-paclitaxel and Gemcitabine as First-line Treatment in Patients With Advanced Pancreatic Adenocarcinoma

Conditions
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Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Ramucirumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent Histologically or cytologically proven pancreatic adenocarcinoma. Metastatic or locally advanced unresectable disease confirmed clinically/radiologically by CT-scan or MRI (Magnetic Resonance Imaging) No prior therapy for metastatic disease. At least one measurable or evaluable lesion as assessed by CT-scan or MRI according to RECIST v1.1 Age 18 years, ECOG Performance status (PS) 0-1 The patient has adequate hepatic function as defined by a total bilirubin 1.5 mg/dL (25.65 μmol/L), and aspartate transaminase (AST) and alanine transaminase (ALT) 2.5 times the upper limit of normal (ULN; or 5.0 times the ULN in the setting of liver metastases) Female patients must commit to using reliable and appropriate methods of contraception during the trial until at least three months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another reliable contraceptive method during the trial until at least 6 months after the end of study treatment. Patients must have a low or intermediate risk of arterial or venous thrombotic events (Khorana risk score 0-2). Patients at a high VTE risk (Khorana RS3) are eligible if they receive LMWH prophylaxis (Appendix D). Exclusion Criteria: The patient has pancreatic cancer with histology other than adenocarcinoma Prior therapy for metastatic disease. Adjuvant Gemcitabine is permitted if 6 or more months have elapsed from last cycle to date of relapse. Exclusive presence of bone metastasis only Concomitant unplanned antitumor therapy Treatment with any other investigational medicinal product within 28 days prior to study entry Other serious and uncontrolled non-malignant chronic disease The patient has documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression. The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal antiinflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325mg/day) is permitted. The patient has experienced grade 3-4 gastrointestinal bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis within 3 months prior to first dose of protocol therapy. Other concomitant or previous malignancy The patient has symptomatic congestive heart failure (CHF; New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia Bowel obstruction The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation. Palliative radiation therapy within 4 weeks prior to registration The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered significant) during the 3 months prior to first dose of protocol therapy. High risk for arterial or venous thrombotic complications as depicted by a Khorana Risk Score higher than 2 and inability to receive prophylaxis with low molecular weight heparin.

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: Ramucirumab+Nab-paclitaxel+Gemcitabine<br>Nab-paclitaxel and Gemcitabine will be administered on days 1, 8 and 15 every 4 weeks for a maximum of 8 cycles. | Drug: Ramucirumab<br>* 8 mg/kg (days 1 and 15, q4w) until disease progression<br>* Other names: Cyramza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Assessment of safety by identifying the Recommended Dose (RD) of the combination of Ramucirumab with Nabpaclitaxel and Gemcitabine. |  | From enrollment up to 90 days after the last administration of any investigational product | 
| Phase II: Overall Response Rate is defined as the proportion of patients with confirmed Complete Response or confirmed Partial Response as best overall response to treatment, based on RECIST v. 1.1 guidelines in the considered analysis population. |  | Up to 33 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | Up to 33 months | 
| Progression-free survival |  | Every 8 weeks until month 8 and then every 12 weeks, up to 33 months | 
| Phase I:Toxicity profile of the combination during the first 2 cycles of therapy |  | From the first administration of study treatment and up to week 8 (during the first 2 cycles of the treatment, each cycle is 28 days) | 
| Phase II: Number of participants with Serious and Non-Serious Adverse Events graded according to National Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 |  | From enrollment up to 33 months. | 
| Investigation of SPARC gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of PTEN gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of MEK gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of AREG gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of EREG gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of VEGF-A gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of VEGF-B gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of PlGF gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of TSP1 gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of MMP2 gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of MMP9 gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months | 
| Investigation of VEGFR1-3 gene mutation, m-RNA and protein expression |  | At baseline, in cycles 1 and 3 (each cycle is 28 days), at maintenance therapy and at the date of first documented progression up to 33 months |