Clinical Trials /

Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-gastric Diseases (PROCEED)

NCT03064490

Description:

This is a single-institution, prospective phase II trial with an initial safety run-in to evaluate the efficacy and safety of neoadjuvant pembrolizumab combined with chemoradiotherapy and adjuvant pembrolizumab in patients with locally advanced esophageal and gastric cancers (EGC). Chemoradiation therapy (45Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of pembrolizumab will be administered as neoadjuvant therapy. These patients will also receive three cycles of adjuvant pembrolizumab after surgical resection

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-gastric Diseases (PROCEED)
  • Official Title: Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-gastric Diseases (PROCEED)

Clinical Trial IDs

  • ORG STUDY ID: Pro00081010
  • NCT ID: NCT03064490

Conditions

  • Locally Advanced Esophageal and Gastric Cancers (EGC)

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaSingle arm interventional study

Purpose

This is a single-institution, prospective phase II trial with an initial safety run-in to evaluate the efficacy and safety of neoadjuvant pembrolizumab combined with chemoradiotherapy and adjuvant pembrolizumab in patients with locally advanced esophageal and gastric cancers (EGC). Chemoradiation therapy (45Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of pembrolizumab will be administered as neoadjuvant therapy. These patients will also receive three cycles of adjuvant pembrolizumab after surgical resection

Detailed Description

      Enrolled patients will receive three doses of neoadjuvant pembrolizumab (200 mg administered
      as an intravenous infusion over 30 minutes every 3 weeks). The first dose of pembrolizumab
      will be administered approximately 14 days prior to initiating radiotherapy. The second dose
      will be administered three weeks later (week 1 of chemoradiation). The third dose will be
      administered 3 weeks later (week 4 of chemoradiotherapy). Pembrolizumab will be given every 3
      weeks and may be given at the same time as systemic therapy. All patients will receive
      radiation treatment (45Gy in 25 fractions at 1.8 Gy/fraction) using image-guided radiation
      therapy with concurrent, weekly carboplatin (AUC 2) and paclitaxel (50mg/m2 of BSA).
      Restaging will be performed per standard of care approximately 4-8 weeks after completing
      chemoradiotherapy. Resection will be performed approximately 6-12 weeks after completing
      chemoradiotherapy per standard of care. Postoperatively, three additional cycles of
      pembrolizumab (200 mg every 3 weeks) will be administered as adjuvant therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Single arm interventional studyOtherSingle arm, non randomized, open label study. Subjects will receive three doses of neoadjuvant pembrolizumab (200 mg administered as an intravenous infusion over 30 minutes every 3 weeks). Pembrolizumab will be administered with weekly standard of care Carboplatin/Paclitaxel concurrent chemo-radiation therapy in the neo-adjuvant setting. Postoperatively, three additional cycles of pembrolizumab (200 mg every 3 weeks) will be administered as adjuvant therapy.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent for the trial.

          2. Be 18 years of age or older on day of signing informed consent.

          3. Has a pathologic diagnosis of invasive esophageal, gastroesophageal or gastric
             adenocarcinoma.

          4. Staging CT CAP or PET/CT shows no evidence of metastatic disease.

          5. EUS for local tumor staging (if ultrasound probe able to traverse tumor).

          6. Have a performance status of 0-2 on the ECOG Performance Scale.

          7. Plan for neoadjuvant chemoradiation.

          8. Demonstrate adequate organ function as defined in the study protocol, all screening
             labs should be performed within 14 days of treatment initiation.

          9. Female subject of childbearing potential should have a negative serum pregnancy within
             48 hours prior to receiving the first dose of study medication.

         10. Female and male subjects of childbearing potential must be willing to use an adequate
             method of contraception as outlined in the Duke Contraception Policy.

        Exclusion Criteria:

          1. 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.

          2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment.

          3. Has a known history of active TB (Bacillus Tuberculosis)

          4. Hypersensitivity to pembrolizumab or any of its excipients.

          5. 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.

          6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy for
             the current diagnosis of EGC.

          7. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer. (all
             patients with prior radiotherapy must be reviewed by the PI to determine if patient is
             eligible).

          8. Has known metastatic disease. Staging CT C/A/P or PET/CT will be mandatory no more
             than 45 days prior to enrollment to evaluate for the presence of metastatic disease.

          9. Has unresectable disease or is medically inoperable.

         10. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with chronic use of disease modifying agents, corticosteroids or
             immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment.

         11. Has known history of, or any evidence of active, non-infectious pneumonitis.

         12. Has an active infection requiring systemic therapy.

         13. 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.

         14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         15. 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.

         16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         18. Has known, active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

         19. Has received a live vaccine within 30 days of planned start of study therapy. 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.

         20. Has a diagnosis of scleroderma.

         21. Has a known history of allogenic stem cell transplant

         22. Has received a solid organ transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response
Time Frame:2 years
Safety Issue:
Description:A two-stage design will be used to test the null hypothesis that the true pCR rate is ≤ 0.30 against the alternative hypothesis that the true pCR rate is ≥ 0.50. This design will allow the trial to stop early to accept the null hypothesis. If there are no more than 4 responders (27%) in the first 15 evaluable patients, the trial will stop to accept the null. Otherwise, an additional 15 evaluable patients will be accrued.

Secondary Outcome Measures

Measure:Safety of the combined drug therapy with radiation therapy.
Time Frame:2 years
Safety Issue:
Description:Toxicity by type and grade will be tabulated. Toxicity rates of interest will be calculated with their 80% confidence intervals. After the first 5 subjects have been accrued, an analysis will be performed to assess acute treatment-related toxicities. If more than 1, grade 3 or greater toxicities definitely related to concurrent pembrolizumab and radiotherapy are observed, then an additional five patients will be added to this treatment arm.If no issues concerning for safety are observed within 30 days of the last dose of neoadjuvant pembrolizumab (cycle 3) for the fifth patient, then the study will continue to accrue.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Duke University

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