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Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8Phase 2NCT04929392

Chemoradiation and Pembrolizumab Followed by Pembrolizumab and Lenvatinib Before Surgery for the Treatment of Non-metastatic Esophageal or Esophageal/Gastroesophageal Junction Cancer

A Phase 2 study testing Carboplatin, Endoscopic Biopsy and External Beam Radiation Therapy in people with Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8 and Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, run by City of Hope Medical Center at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

This phase II trial studies the effect of chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery in treating patients with esophageal or esophageal/gastroesophageal junction cancer that has not spread to other places in the body (non-metastatic). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Carboplatin, Endoscopic Biopsy and External Beam Radiation Therapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3 participants
Where
1 siteUnited States
Study dates
25 Jan 2022to 25 Apr 2027
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Documented informed consent of the participant and/or legally authorized representative
  • Agreement to allow the use of archival tissue from diagnostic tumor biopsies
  • If unavailable, exceptions may be granted only with study principal investigator (PI) approval
  • Age >= 18 years
  • Eastern Cooperative Oncology Group (ECOG) =< 1
  • Non-metastatic cancer of the esophagus OR esophagus and gastroesophageal junction (GEJ; tumor extending =< 2 cm into the stomach)
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  • Confirmed stage I (T1N1 only)-IVA diagnosis of one of the following:
  • Squamous cell; OR
  • Adenocarcinoma; OR
  • Mixed adenosquamous carcinoma
  • Deemed appropriate for neoadjuvant chemoradiation by the multidisciplinary team (surgeon, medical oncologist, and radiation oncologist)
  • Chemotherapy defined as weekly carboplatin/paclitaxel; AND
  • Radiation defined as external beam radiotherapy defined as: 50.4 Gy as per institutional and national treatment guidelines
  • Deemed appropriate for esophagectomy or repeat endoscopic biopsies if non-operative management is pursued
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (performed within 14 days prior to day 1 of study participation/ 1st endoscopic biopsy unless otherwise stated)
  • Platelets >= 100,000/mm^3 (performed within 14 days prior to day 1 of study participation/ 1st endoscopic biopsy unless otherwise stated)
  • Serum total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN if total bilirubin levels > 1.5 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
  • Aspartate aminotransferase (AST) =< 2 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
  • Alanine aminotransferase (ALT) =< 2 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
  • Creatinine =< 1.5 x ULN OR for patients with creatinine > 1.5 x ULN creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
  • Female of childbearing potential only: Negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
  • Agreement by women of childbearing potential (WOCBP) and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 120 days after the last dose of protocol therapy
  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Who cannot join

  • Immune checkpoint inhibitor(s) (e.g. anti-PD-1, anti-CTLA4)
  • Multi-tyrosine kinase inhibitor(s) (e.g. lenvatinib)
  • Radiotherapy within 21 days prior to day 1 of study participation
  • Investigational agent within 21 days prior to day 1 of study participation
  • Live-virus vaccination within 30 days prior to day 1 of study participation
  • Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 21 days of study participation
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  • Chronic systemic steroid therapy or on any other form of immunosuppressive medication
  • Coumarin-based anticoagulants
  • Unstable or untreated brain/leptomeningeal metastasis
  • Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
  • Severe hypersensitivity reaction to treatment with another antibody and/or hypersensitivity to lenvatinib and/or any of its excipients
  • Active autoimmune disease that has required systemic treatment in the past 2 years
  • Known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C (with confirmation of negative hepatitis B surface antigen [HBSAg], hepatitis B virus [HBV] polymerase chain reaction [PCR], and hepatitis C virus [HCV] PCR)
  • History of pneumonitis (non-infectious) that required steroids or current pneumonitis
  • Known history of active tuberculosis
  • Diagnosed with or treated for cancer within the previous two years, other than histologies listed in inclusion criteria or non-melanoma carcinoma of the skin
  • Female only: Pregnant or breastfeeding
  • Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
  • Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • City of Hope Medical Center

    Duarte, California, 91010

Other trials in United States

About this study

Official title: A Phase 2 Trial of Neoadjuvant Chemoradiation With Pembrolizumab Followed by Pembrolizumab With Lenvatinib in Esophageal/Gastroesophageal Junction Squamous Cell and Adenocarcinomas

This phase II trial studies the effect of chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery in treating patients with esophageal or esophageal/gastroesophageal junction cancer that has not spread to other places in the body (non-metastatic). Pembrolizumab is an immunotherapy drug that works by harnessing the immune system to attack cancer. Lenvatinib is an anti-cancer drug that works by stopping or slowing down the growth of cancer cells. Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery may kill more tumor cells.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To evaluate pathologic complete response rate (path CR) and complete clinical response rate (clinical CR) at 14 weeks after starting chemoradiotherapy.

SECONDARY OBJECTIVES:

  1. To assess safety and tolerability of pembrolizumab and lenvatinib in this patient population.

II. To establish that pembrolizumab + lenvatinib will increase immune response via increased expression of the 18 gene pro-immune response signature measured using the Nanostring platform on tumor tissue biopsies.

III. To evaluate disease-free survival (DFS) and overall survival (OS) in this study population.

EXPLORATORY OBJECTIVES:

  1. To identify through an integrated genomic sequencing approach (MHC-PepSeq) the presence of tumor mutations able to elicit neo-antigen-specific immunity in this population expected to be predominated by microsatellite stability (MSS) tumors.

II. To correlate temporal variations in circulating tumor deoxyribonucleic acid (ctDNA) representing immunogenic and non-immunogenic mutations as pharmacodynamic immune markers.

III. To correlate diversity in the gut microbiome with path CR and clinical CR in this study population.

OUTLINE:

CHEMORADIATION PHASE: Patients receive carboplatin intravenously (IV) and paclitaxel IV once a week (QW) for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo external beam radiation therapy (EBRT) over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.

WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate orally (PO) once daily (QD) at weeks 3-6 in the absence of disease progression or unacceptable toxicity.

SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.

After completion of study treatment, patients are followed up at 90 days, then for up to 3 years.

Being tested
Carboplatin, Endoscopic Biopsy, External Beam Radiation Therapy, Lenvatinib Mesylate, Paclitaxel
Medical subject headings
Adenocarcinoma Of Esophagus, Esophageal Squamous Cell Carcinoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CarboplatinDrug

    Also called Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino

    Given IV

  • Endoscopic BiopsyProcedure or surgery

    Also called Endoscopy and Biopsy

    Undergo endoscopic biopsy

  • External Beam Radiation TherapyRadiation

    Also called Definitive Radiation Therapy, EBRT, External Beam Radiation, External Beam Radiotherapy

    Undergo EBRT

  • Lenvatinib MesylateDrug

    Also called 4-[3-Chloro-4-(N''-cyclopropylureido)phenoxy]7-methoxyquinoline-6-carboxamide Mesylate, E7080, Lenvima, Multi-Kinase Inhibitor E7080

    Given PO

  • PaclitaxelDrug

    Also called Anzatax, Asotax, Bristaxol, Praxel

    Given IV

  • PembrolizumabBiological

    Also called Keytruda, Lambrolizumab, MK-3475, SCH 900475

    Given IV

  • ResectionProcedure or surgery

    Also called Surgical Resection

    Undergo surgical resection

Study groups in NCT04929392
Study groupRoleWhat they receive
Treatment (chemoradiation, pembrolizumab, lenvatinib)ExperimentalCHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
Receives: Drug: Carboplatin; Procedure: Endoscopic Biopsy; Radiation: External Beam Radiation Therapy; Drug: Lenvatinib Mesylate; Drug: Paclitaxel; Biological: Pembrolizumab; Procedure: Resection

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Pathological Complete Response (CR)

    Defined as no residual cancer cells, including lymph nodes under pathologic examination of the surgically resected specimen and/or a Tumor Regression Score of 0 by the College of American Pathologist (CAP) Cancer Protocol for Esophageal Carcinoma. Pathological CR rate will be estimated by the proportion of patients achieving pathological CR, along with the 95% exact binomial confidence interval.

    Measured: At 14 weeks after starting protocol chemoradiotherapy

  2. Clinical Complete Response (CR)

    Defined as no radiographic evidence of disease on positron emission tomography /computed tomography or CT imaging. Clinical CR rate will be estimated by the proportion of patients achieving clinical CR, along with the 95% exact binomial confidence interval.

    Measured: At 14 weeks after starting protocol chemoradiotherapy

Secondary outcomes (4)

  1. Number of Participants With Immune-mediated Tumor Cytotoxicity

    For each patient, tumor cytotoxic T cell infiltration will be compared between the post-chemoradiation biopsy (pre-pembrolizumab/lenvatinib) and post-treatment (definitive surgery or follow up biopsies if clinical CR) via increased expression of the 18 gene proimmune response signature measured using the Nanostring platform on tumor tissue biopsies. Participants who had changes in these measures during and after treatment will be summarized by descriptive statistics.

    Measured: Up to 3 years

  2. Number of Participants With Adverse Events

    Assessed per Common Terminology Criteria for Adverse Events version 5.0.

    Measured: Adverse events were assessed from the time of initial treatment until 90 days post-last dose of protocol therapy, an average of 49 days.

  3. Disease-free Survival (DFS)

    DFS will be determined using the Kaplan-Meier method.

    Measured: Up to 3 years. From initiation of treatment to the first occurrence of cancer relapse or death from any cause.

  4. Overall Survival (OS)

    OS will be determined using the Kaplan-Meier method.

    Measured: Up to 3 years. From start of treatment to time of death.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jun 2021
  2. Study start25 Jan 2022
  3. Primary completion9 Dec 2022
  4. Study completion25 Apr 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04929392
Sponsor's protocol ID
20742
Other IDs
NCI-2021-03223, 20742, P30CA033572
Status last verified
May 2026
First submitted
11 Jun 2021
Last updated
23 Jun 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided

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