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Novel SEQUEnced Immunotherapy With Anti-angiogenesis and Chemotherapy in Advanced gastroesophageaL Adenocarcinoma (SEQUEL)

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ClinicalTrials.gov Identifier: NCT04069273
Recruitment Status : Recruiting
First Posted : August 28, 2019
Last Update Posted : July 16, 2021
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Mayo Clinic
Information provided by (Responsible Party):
Harry H Yoon, Hoosier Cancer Research Network

Tracking Information
First Submitted Date  ICMJE August 22, 2019
First Posted Date  ICMJE August 28, 2019
Last Update Posted Date July 16, 2021
Actual Study Start Date  ICMJE December 1, 2020
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 23, 2019)
Evaluate the best overall response rate (BORR) of each arm with historical control [ Time Frame: 3 years ]
BORR is defined as the number of best responses (including rates of complete response [CR], partial response [PR], disease control [DCR], stable disease [SD], progressive disease [PD]) divided by the total number of evaluable patients.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2019)
  • Evaluate BORR pooling Arm A and B. [ Time Frame: 3 years ]
    BORR (including rates of complete response [CR], partial response [PR], disease control [DCR], stable disease [SD], progressive disease [PD])
  • Evaluate duration of response pooling Arm A and B. [ Time Frame: 3 years ]
    Duration of overall response-the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since treatment started).
  • Evaluate irPFS pooling Arm A and B. [ Time Frame: 3 years ]
    irPFS is defined as time from randomization until documented progression per irRECIST
  • Evaluate overall survival (OS) pooling Arm A and B. [ Time Frame: 3 years ]
    Overall survival defined date of randomization until date of death from any cause
  • Evaluate duration of response on RAM/paclitaxel-based combination therapy following irRECIST PD on PEM, pooling Arm A and B. [ Time Frame: 3 years ]
    Duration of overall response-the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since treatment started).
  • Compare BORR of Arm A vs Arm B [ Time Frame: 3 years ]
    BORR (including rates of complete response [CR], partial response [PR], disease control [DCR], stable disease [SD], progressive disease [PD])
  • Compare duration of response of Arm A vs Arm B [ Time Frame: 3 years ]
    Duration of overall response-the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since treatment started).
  • Compare immune-related progression free survival [irPFS]) of Arm A vs Arm B [ Time Frame: 3 years ]
    irPFS is defined as time from randomization until documented progression per irRECIST
  • Assess the frequency and severity of adverse events [ Time Frame: 3 years ]
    Toxicities will be measured in frequency and severity using CTCAE criteria 4.03
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Novel SEQUEnced Immunotherapy With Anti-angiogenesis and Chemotherapy in Advanced gastroesophageaL Adenocarcinoma
Official Title  ICMJE Phase 2 Study of Novel SEQUEnced Immunotherapy (Pembrolizumab) With Anti-angiogenesis and Chemotherapy in Advanced Gastric and gastroesophageaL Junction (GEJ) Adenocarcinoma
Brief Summary This randomized phase 2 study will evaluate 2 novel immunotherapy combinations in which pembrolizumab is integrated with ramucirumab and paclitaxel in patients with advanced gastric and GEJ adenocarcinoma. A total of 58 patients will be enrolled to the study. Each arm will have 26 patients. Although the study has a randomized design, patients in both arms will receive study drug (pembrolizumab).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Gastric Cancer
  • GastroEsophageal Cancer
  • Adenocarcinoma
Intervention  ICMJE
  • Drug: Pembrolizumab Monotherapy
    Pembrolizumab 200 mg IV
    Other Name: Keytruda
  • Drug: Ramucirumab
    Ramucirumab 8 mg/kg IV
    Other Name: Cyramza
  • Drug: Paclitaxel
    Paclitaxel 80 mg/m2 IV
    Other Name: Taxol
Study Arms  ICMJE
  • Experimental: Arm A (Ramucirumab and Paclitaxel)

    All patients receive pembrolizumab monotherapy (generally once every 3 weeks). Then this is followed by ramucirumab + paclitaxel (study drug[s] are generally given once per week). As study treatment moves forward, a patient-tailored disease-specific algorithm is applied in which pembrolizumab is re-introduced and integrated with ramucirumab + paclitaxel if clinical benefit is anticipated.

    NOTE: All registered patients receive pembrolizumab, then patients are randomized to Arm A (ramucirumab + paclitaxel with patient-tailored disease-specific potential re-introduction of pembrolizumab with ramucirumab + paclitaxel) or Arm B (concurrent pembrolizumab with ramucirumab + paclitaxel)

    Interventions:
    • Drug: Pembrolizumab Monotherapy
    • Drug: Ramucirumab
    • Drug: Paclitaxel
  • Experimental: Arm B (Pembolizumab, Ramucirumab and Paclitaxel)
    All patients receive pembrolizumab monotherapy (generally once every 3 weeks), which is followed by pembrolizumab + ramucirumab + paclitaxel (study drug[s] are generally given once per week).
    Interventions:
    • Drug: Pembrolizumab Monotherapy
    • Drug: Ramucirumab
    • Drug: Paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 23, 2019)
58
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • Age ≥ 18 years at the time of consent.
  • ECOG Performance Status (PS) of 0-1within 28 days prior to registration. NOTE: Within 0-3 days prior to the anticipated C1D1, ECOG PS must be 0-1.
  • Archived tumor tissue must be available and identified during screening and shipped after subject registration. If archived tissue is not available and the subject is not undergoing a standard of care biopsy, the subject is not eligible for trial participation.
  • PD-L1 results are required, if available. If PD-L1 testing has not been done, it should be ordered as standard of care prior to C1D1. PD-L1 testing must be performed by a CLIA certified lab using the Dako 22C3 antibody.
  • Histologically or cytologically proven adenocarcinoma of the stomach or GEJ.
  • Metastatic, recurrent, or locally advanced unresectable disease.
  • Intolerant of or progressed on at least one prior line of therapy for metastatic disease. NOTE: Neoadjuvant or adjuvant therapy administered < 12 months prior to diagnosis of recurrent disease counts as one line of therapy.
  • Measurable disease per RECIST v1.1
  • Candidate for pembrolizumab, ramucirumab, and paclitaxel
  • Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to registration. NOTE: Labs must also be obtained within 10 days prior to C1D1 treatment.

    • Absolute Neutrophil Count (ANC) ≥ 1,100/mm3
    • Hemoglobin (Hgb) ≥ 8.5 g/dL without transfusion or EPO dependency
    • Platelets ≥ 100,000 / mcL
    • Creatinine OR Calculated creatinine clearance1 ≤ 1.5 x upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN
    • Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN OR total bilirubin ≤ 2 x ULN if liver metastases are present (patients with Gilbert's syndrome are allowed)
    • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 x ULN for subjects with liver metastases
    • Albumin > 2.5 g/dL
  • Willingness to provide tissue and blood samples for correlative research purposes. NOTE: Enrollment in parallel biopsy protocol, if open for enrollment, is required. Parallel biopsy protocol entitled: "Exploration of tumor biology in patients with metastatic esophageal and gastric cancer (biorepository protocol for prospective tissue collection)".
  • Females of childbearing potential must have a negative pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
  • Females of childbearing potential and males must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent (females)/prior to C1D1 (males) until 120 days after treatment discontinuation. See Section 5.6 for contraception options.
  • Willingness to return to the enrolling institution for follow up

Exclusion Criteria:

  • Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease (relevant for ramucirumab).
  • Any of the following cardiac criteria (relevant for ramucirumab):

    • Mean resting corrected QT interval (QTc using Fridericia's formula) > 470 msec.
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250msec.
    • Symptomatic heart failure, uncontrolled hypokalemia despite repletion, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives. NOTE: Factors that increase risk of QTc prolongation or risk of arrhythmia, such as concomitant medications, may require increased monitoring during Combination Therapy (See Section 7).
    • The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.
    • The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
  • The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy (relevant for ramucirumab).
  • 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 (relevant for ramucirumab).
  • Any hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer (relevant for ramucirumab).
  • The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation (relevant for ramucirumab).
  • The patient has a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy (relevant for ramucirumab).
  • The patient has undergone major surgery within 28 days prior to first dose of protocol therapy prior to the first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial (relevant for ramucirumab).
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. NOTE: Inhaled steroids or steroid injections for joint disease are allowed.
  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
  • Disease progression according to RECIST v1.1 or irRECIST, or treatment intolerance, during prior therapy with an anti-PD-1, anti-PD-L1, or anti- PD-L2 agent. NOTE: Stable or responsive disease on anti-PD-1/L1-L2 therapy (without concurrent cytotoxic therapy) is allowed.
  • Weight loss ≥5% during prior anti-PD-1, anti-PD-L1, or anti- PD-L2-containing therapy (from time of initiation of such therapy to most recent dose).
  • Prior therapy combining anti-angiogenesis agent with cytotoxic agent(s). NOTE: Prior single-agent anti-angiogenesis therapy (eg, ramucirumab monotherapy) is allowed.
  • Patients known to be HIV positive.
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Prior severe allergic reactions to a monoclonal antibody or hypersensitivity to pembrolizumab or any of its excipients.
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 3 weeks earlier.
  • Other active malignancy which requires current treatment and which in the opinion of the site investigator is likely to interfere with evaluation of disease assessment. NOTE: Continuation of hormonal therapies is allowed.
  • Patients with known active central nervous system (CNS) metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  • Uncontrolled intercurrent illness which in the opinion of the investigator poses unacceptably high risk when combined with study treatment, including but not limited to the following:

    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Severely impaired lung function
    • Known history of active TB (Bacillus Tuberculosis)
    • Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (NOTE: Optimal glycemic control should be achieved before starting trial therapy.)
    • Significant underlying liver disease such as severe cirrhosis or hepatic impairment
    • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Has an active infection requiring systemic therapy prior to therapy initiation.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  • Has known history of or any evidence of active, non-infectious pneumonitis.
  • Currently uncontrolled hyper/hypothyroidism or hyper/hypocortism if in the opinion of the investigator they pose unacceptably high risk when combined with study treatment.
  • Received live vaccine ≤ 30 days prior to registration. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  • Prior pancreatitis that was symptomatic or required medical intervention ≤ 6 months prior to registration (known toxicity of pembrolizumab).
  • Prior enteritis that was symptomatic or required medical intervention ≤ 6 months prior to registration (known toxicity of pembrolizumab).
  • Pre-existing motor or sensory neurotoxicity grade 3 or higher.
  • For patients who received palliative RT, there must be no evidence of disease progression on clinical or imaging exams for at least two weeks prior to first dose of treatment.
  • Parenteral or oral corticosteroids in the last two weeks prior to starting study treatment.
  • Prior solid organ or allogeneic transplant.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Harry H Yoon, MD, MHS 507-284-2511 Yoon.Harry@mayo.edu
Contact: LeaEtta Hyer 317-634-5842 ext 62 lhyer@hoosiercancer.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04069273
Other Study ID Numbers  ICMJE HCRN GI18-333
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Harry H Yoon, Hoosier Cancer Research Network
Study Sponsor  ICMJE Harry H Yoon
Collaborators  ICMJE
  • Merck Sharp & Dohme Corp.
  • Mayo Clinic
Investigators  ICMJE
Principal Investigator: Harry H Yoon, MD, MHS Mayo Clinic
PRS Account Hoosier Cancer Research Network
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP