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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04069273
Recruitment Status : Not yet recruiting
First Posted : August 28, 2019
Last Update Posted : July 31, 2020
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 31, 2020
Estimated Study Start Date  ICMJE August 2020
Estimated Primary Completion Date May 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 (SEQUEL)
Official Title  ICMJE Phase 2 Study of Novel SEQUEnced Immunotherapy (Pembrolizumab) With Anti-angiogenesis and Chemotherapy in Advanced Gastric and gastroesophageaL Junction (GEJ) Adenocarcinoma (SEQUEL)
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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: August 23, 2019)
58
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2023
Estimated Primary Completion Date May 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
    • 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
  • Females of childbearing potential must have a negative serum pregnancy test within 72 hours days 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 activity or to use 2 forms of effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.
  • Willingness to return to the enrolling institution for follow up
  • Willingness to provide tissue and blood samples for correlative research purposes.

Exclusion Criteria:

  • 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.
  • Patients known to be HIV positive.
  • 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.
  • Has received prior therapy with:

    • an anti-PD-1, anti-PD-L1, or anti- PD-L2 agent
    • has received prior anti-angiogenesis therapy.
  • 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 4 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 4 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: Julia Beck 3176345842 ext 62 jbeck@hoosiercancer.org
Listed Location Countries  ICMJE Not Provided
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 2020

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