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

• ClinicalTrials.gov Identifier: NCT03064490
• Recruitment Status: Active, not recruiting
• First Posted: February 27, 2017
• Last Update Posted: December 8, 2022
• Sponsor: Duke University
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: February 22, 2017
• First Posted Date: February 27, 2017
• Last Update Posted Date: December 8, 2022
• Actual Study Start Date: October 17, 2017
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 24, 2017)

Pathologic complete response [ Time Frame: 2 years ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 24, 2017)

Safety of the combined drug therapy with radiation therapy. [ Time Frame: 2 years ]

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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)
• Brief Summary: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Locally Advanced Esophageal and Gastric Cancers (EGC)

Intervention

Drug: Pembrolizumab

Neoadjuvant Pembrolizumab ( 3 cycles) administered concurrently with weekly Carboplatin and Paclitaxel and daily radiation therapy; followed by surgical resection and adjuvant Pembrolizumab ( 3 cycles)

Other Name: Keytruda

Study Arms

Single arm interventional study

Single 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.

Intervention: Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 24, 2017): 38
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2024
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

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. Have a performance status of 0-2 on the ECOG Performance Scale.
6. Plan for neoadjuvant chemoradiation.
7. Demonstrate adequate organ function as defined in the study protocol, all screening labs should be performed within 14 days of treatment initiation.
8. Female subject of childbearing potential should have a negative serum pregnancy within 48 hours prior to receiving the first dose of study medication.
9. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03064490
• Other Study ID Numbers: Pro00081010
• Has Data Monitoring Committee: No

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

• Plan to Share IPD: No

• Current Responsible Party: Duke University
• Original Responsible Party: Same as current
• Current Study Sponsor: Duke University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Manisha Palta, MD; Duke University

• PRS Account: Duke University
• Verification Date: December 2022