AIO-STO-0218: Avelumab + Paclitaxel/ Ramucirumab (RAP) as Second Line Treatment in Gastro-esophageal Adenocarcinoma

Sponsor

P. C. Thuss-Patience (Other)

Overall Status

Recruiting

CT.gov ID

NCT03966118

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Avelumab + Paclitaxel/ Ramucirumab as second line treatment in gastro-esophageal adenocarcinoma following first-line therapy with platinum and fluoropyrimidine doublet with or without anthracycline, docetaxel or trastuzumab

Condition or Disease	Intervention/Treatment	Phase
Gastroesophageal Junction Adenocarcinoma Adenocarcinoma of the Stomach	Drug: Avelumab Drug: Ramucirumab Drug: Paclitaxel	Phase 2

Detailed Description

Patients with adenocarcinoma of the gastro-esophageal junction or the stomach who have documented progression after being treated with a 1st line chemotherapy which contained at least a platinum and 5-FU (5-Flourouracil)can be included. All patients will receive a standard second line therapy with paclitaxel and ramucirumab plus the investigational drug avelumab, a checkpoint inhibitor. Clinical and radiographic assessment will be performed regularly. Patients will be treated until disease progression, untolerable toxicity or withdrawal of consent.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

59 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Avelumab + Paclitaxel / RamucirumabAvelumab + Paclitaxel / Ramucirumab

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Avelumab + Paclitaxel/ Ramucirumab as Second Line Treatment in Gastro-esophageal Adenocarcinoma: a Phase II Trial of the AIO (The RAP-Trial)

Actual Study Start Date :

Apr 1, 2019

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ramucirumab + Avelumab + Paclitaxel Single-Arm	Drug: Avelumab Avelumab 1mg/kg Day 1 and Day 15 of a 28-day cycle Drug: Ramucirumab Ramucirumab 8mg/kg on Day 1 and Day 15 of a 28-day cycle Drug: Paclitaxel Paclitaxel 80mg/m2 on Day 1, Day 8 and Day 15 of a 28-day cycle

Arm

Intervention/Treatment

Experimental: Ramucirumab + Avelumab + Paclitaxel

Single-Arm

Drug: Avelumab

Avelumab 1mg/kg Day 1 and Day 15 of a 28-day cycle

Drug: Ramucirumab

Ramucirumab 8mg/kg on Day 1 and Day 15 of a 28-day cycle

Drug: Paclitaxel

Paclitaxel 80mg/m2 on Day 1, Day 8 and Day 15 of a 28-day cycle

Outcome Measures

Primary Outcome Measures

Overall Survival Rate at 6 months [6 months]
patients alive at 6 months

Secondary Outcome Measures

Overall Survival [40 months]
patients alive using Kaplan Meyer
Overall Survival Rate at 12 months [12 months]
patients alive at 12 months
Progression Free Survival [40 months]
Patients showing progressive disease
Progression Free Survival Rate at 6 months according to RECIST v1.1 [6 months]
Patients showing progressive disease at 6 months
Progression Free Survival Rate at 12 months according to RECIST v1.1 [12 months]
Patients showing progressive disease at 12 months
Number of participants with treatment related adverse events (AE) as assessed by common toxicity criteria CTC AE v5.0 [40 months]
Patients reported with adverse events
Number of participants to whom the treatment could me administered as planned (feasibility). [40 months]
number of patients who received treatment
Best response according to RECIST v1.1 [40 months]
Proportion of patients who show response
Confirmed response rate according to RECIST v1.1 [40 months]
Proportion of patients who show confirmed response
Duration of response [40 months]
time how long response lasts
Amount of Tumor infiltrating lymphocytes and TCRβ & IgH; clonal evolution [40 months]
liquid biopsy and next generation sequencing
Subgroup analyses: number of participants with Programmed Death receptor Ligand 1 (PD-L1) positive tumors. [40 months]
number of patients with PD-L1 positive tumors in pathology assessment
Progression Free Survival (PFS) according to modified RECIST [40 months]
Proportion of patients who show progressive disease
Overall Response Rate (ORR) according to modified RECIST [40 months]
Proportion of patients responding

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed written informed consent
Male or female ≥ 18 years of Age
Histologically proven gastric adenocarcinoma including adenocarcinoma of the esophagogastric junction
Metastatic or locally advanced disease, not amenable to potentially curative resection
Documented objective radiological or clinical disease progression during or within 6 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline, docetaxel or trastuzumab. Neoadjuvant/adjuvant treatment is not counted unless progression occurs <6 months after completion of the treatment. In these cases neoadjuvant/adjuvant treatment is counted as first line.
Measurable or non-measurable but evaluable disease determined using guidelines RECIST 1.1
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Life expectancy > 12 weeks
Adequate hematological, hepatic and renal functions:
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Platelet count ≥ 100 x 109/L
Hemoglobin ≥ 9 g/dl (may have been transfused)
Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) and AST and ALT ≤ 2.5 x ULN in absence of liver metastases, or ≤ 5 x ULN in presence of liver metastases; AP ≤ 5 x ULN
Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
Urinary protein ≤ 1+ on dipstick or routine urinalysis (UA; if urinedipstick or routine analysis is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours to allow participation in this protocol)
Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1,5 ULN, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy.
Women of child-bearing potential must have a negative urine or serum pregnancy test
Highly effective contraception for both male and female subjects throughout the study and for at least 30 days after last avelumab and at least 3 months after last ramucirumab treatment administration if the risk of conception exists
Ability to comply with scheduled assessments and with management of toxicities.

Exclusion Criteria:

Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been effectively treated. Patients curatively treated for any other malignancy and disease-free for at least 5 years will be discussed with the sponsor before inclusion
Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol
Previous therapy with, paclitaxel or ramucirumab or pretreatment with a PD-1, PD-L1 Inhibitor
Current treatment with any anti-cancer therapy ≤ 2 weeks prior to study treatment start unless rapidly progressing disease is measured
Previous exposure to a VEGF (vascular endothelial growth factor) or VEGFR inhibitor or any antiangiogenic agent, or prior enrolment in this study
Major surgical procedure, open biopsy or significant traumatic injury within 4 weeks prior to start of study treatment; anticipation of need for major surgical procedure (e.g. impending bowel obstruction) during the course of the study
Grade 3-4 GI bleeding within 3 months prior to enrollment
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
Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
Known brain or leptomeningeal metastases
Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3)
Other serious illness or medical conditions prior to study drug administration
Clinically significant (i.e., active) cardiovascular disease:

cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication

Uncontrolled or poorly controlled hypertension despite optimal medical therapy
Current history of chronic diarrhea
Active disseminated intravascular coagulation
History of gastrointestinal perforation, fistulae or any clinically relevant arterial thromboembolic event within 6 months
Active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive study drug
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
Prior organ transplantation including allogenic stem-cell transplantation
Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
Current use of immunosuppressive medication,

EXCEPT for the following:

intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication
short term steroids to prevent chemotherapy induced Nausea
The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted
Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines
Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days but at least 5 half-lives of the IMP prior to treatment start
Known drug abuse/ alcohol abuse
Persisting toxicity related to prior therapy (NCI CTCAE v. 5.0 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable
Subject pregnant or breast feeding, or planning to become pregnant within 3 months after the end of Treatment
Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 30 days (male or female) with avelumab and 3 months with ramucirumab after the end of Treatment
Patients known to have a HER2 positive cancer who have not been treated already with a HER2 targeting Agent
Patients with a psychiatric illness or patients imprisoned or working in the Institution of the treating physician.