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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

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).

Condition or disease Intervention/treatment Phase
Gastric Cancer GastroEsophageal Cancer Adenocarcinoma Drug: Pembrolizumab Monotherapy Drug: Ramucirumab Drug: Paclitaxel Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Novel SEQUEnced Immunotherapy (Pembrolizumab) With Anti-angiogenesis and Chemotherapy in Advanced Gastric and gastroesophageaL Junction (GEJ) Adenocarcinoma (SEQUEL)
Estimated Study Start Date : August 2020
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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)

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

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).
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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])

  2. 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).

  3. Evaluate irPFS pooling Arm A and B. [ Time Frame: 3 years ]
    irPFS is defined as time from randomization until documented progression per irRECIST

  4. 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

  5. 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).

  6. 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])

  7. 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).

  8. 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

  9. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04069273


Contacts
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Contact: Harry H Yoon, MD, MHS 507-284-2511 Yoon.Harry@mayo.edu
Contact: Julia Beck 3176345842 ext 62 jbeck@hoosiercancer.org

Sponsors and Collaborators
Harry H Yoon
Merck Sharp & Dohme Corp.
Mayo Clinic
Investigators
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Principal Investigator: Harry H Yoon, MD, MHS Mayo Clinic
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Responsible Party: Harry H Yoon, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT04069273    
Other Study ID Numbers: HCRN GI18-333
First Posted: August 28, 2019    Key Record Dates
Last Update Posted: July 31, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Paclitaxel
Pembrolizumab
Ramucirumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological