Clinical Trials /

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

NCT04069273

Description:

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).

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Novel SEQUEnced Immunotherapy With Anti-angiogenesis and Chemotherapy in Advanced gastroesophageaL Adenocarcinoma (SEQUEL)
  • Official Title: Phase 2 Study of Novel SEQUEnced Immunotherapy (Pembrolizumab) With Anti-angiogenesis and Chemotherapy in Advanced Gastric and gastroesophageaL Junction (GEJ) Adenocarcinoma (SEQUEL)

Clinical Trial IDs

  • ORG STUDY ID: HCRN GI18-333
  • NCT ID: NCT04069273

Conditions

  • Gastric Cancer
  • GastroEsophageal Cancer
  • Adenocarcinoma

Interventions

DrugSynonymsArms
Pembrolizumab MonotherapyKeytrudaArm A (Ramucirumab and Paclitaxel)
RamucirumabCyramzaArm A (Ramucirumab and Paclitaxel)
PaclitaxelTaxolArm A (Ramucirumab and Paclitaxel)

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Arm A (Ramucirumab and Paclitaxel)ExperimentalAll 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)
  • Pembrolizumab Monotherapy
  • Ramucirumab
  • Paclitaxel
Arm B (Pembolizumab, Ramucirumab and Paclitaxel)ExperimentalAll 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).
  • Pembrolizumab Monotherapy
  • Ramucirumab
  • Paclitaxel

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate the best overall response rate (BORR) of each arm with historical control
Time Frame:3 years
Safety Issue:
Description: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

Measure:Evaluate BORR pooling Arm A and B.
Time Frame:3 years
Safety Issue:
Description:BORR (including rates of complete response [CR], partial response [PR], disease control [DCR], stable disease [SD], progressive disease [PD])
Measure:Evaluate duration of response pooling Arm A and B.
Time Frame:3 years
Safety Issue:
Description: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).
Measure:Evaluate irPFS pooling Arm A and B.
Time Frame:3 years
Safety Issue:
Description:irPFS is defined as time from randomization until documented progression per irRECIST
Measure:Evaluate overall survival (OS) pooling Arm A and B.
Time Frame:3 years
Safety Issue:
Description:Overall survival defined date of randomization until date of death from any cause
Measure:Evaluate duration of response on RAM/paclitaxel-based combination therapy following irRECIST PD on PEM, pooling Arm A and B.
Time Frame:3 years
Safety Issue:
Description: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).
Measure:Compare BORR of Arm A vs Arm B
Time Frame:3 years
Safety Issue:
Description:BORR (including rates of complete response [CR], partial response [PR], disease control [DCR], stable disease [SD], progressive disease [PD])
Measure:Compare duration of response of Arm A vs Arm B
Time Frame:3 years
Safety Issue:
Description: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).
Measure:Compare immune-related progression free survival [irPFS]) of Arm A vs Arm B
Time Frame:3 years
Safety Issue:
Description:irPFS is defined as time from randomization until documented progression per irRECIST
Measure:Assess the frequency and severity of adverse events
Time Frame:3 years
Safety Issue:
Description:Toxicities will be measured in frequency and severity using CTCAE criteria 4.03

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Harry H Yoon

Last Updated

December 10, 2020