Immunotherapy + Anti-angiogenesis + Chemotherapy for Gastroesophageal Cancer

(SEQUEL Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Harry H Yoon, MD, MHS

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Harry H Yoon

Must be taking: Pembrolizumab, Ramucirumab, Paclitaxel

Must not be taking: Antidepressants, Immunosuppressants

Disqualifiers: ILD, Cardiac issues, Autoimmune, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial uses a combination of drugs to treat cancer patients who may not respond to standard treatments. The drugs help the immune system fight cancer, block blood supply to tumors, and stop cancer cells from dividing.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that certain medications may require increased monitoring during the combination therapy phase. It's best to discuss your current medications with the trial investigator.

What data supports the effectiveness of the drug combination of immunotherapy, anti-angiogenesis, and chemotherapy for gastroesophageal cancer?

Research shows that using ramucirumab (an anti-angiogenesis drug) with paclitaxel (a chemotherapy drug) after immunotherapy can lead to better outcomes in patients with advanced gastroesophageal cancer, including longer survival and reduced tumor size. Pembrolizumab (an immunotherapy drug) is also approved for treating advanced esophageal or gastroesophageal cancer, indicating its effectiveness in this context. ^{1 2 3 4 5}

Is the combination of immunotherapy, anti-angiogenesis, and chemotherapy safe for treating gastroesophageal cancer?

The combination of ramucirumab (Cyramza) and paclitaxel (Taxol) has been shown to be generally safe in clinical trials for advanced gastric or gastroesophageal cancer, with common side effects including high blood pressure, fatigue, and diarrhea. Pembrolizumab (Keytruda) is also approved for use with chemotherapy in esophageal cancer, indicating its safety in similar conditions. ^{2 4 6 7 8}

What makes the combination of Paclitaxel, Pembrolizumab, and Ramucirumab unique for treating gastroesophageal cancer?

This treatment combines immunotherapy (Pembrolizumab), anti-angiogenesis (Ramucirumab), and chemotherapy (Paclitaxel) to target cancer in multiple ways, potentially improving outcomes for patients with advanced gastroesophageal cancer. Ramucirumab is already used as a second-line treatment, and combining it with Pembrolizumab, an immunotherapy drug, may enhance the body's immune response against cancer cells. ^{3 4 9 10 11}

Research Team

Harry H Yoon, MD, MHS

Principal Investigator

Mayo Clinic

Eligibility Criteria

Adults with advanced stomach or gastroesophageal cancer, good organ function, and an ECOG Performance Status of 0-1. They must provide tissue samples, have measurable disease per RECIST v1.1, not be pregnant or breastfeeding, use effective contraception if of childbearing potential, and agree to follow-up visits.

Inclusion Criteria

Females of childbearing potential and males must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent (females)/prior to C1D1 (males) until 120 days after treatment discontinuation

I am a woman who can have children and have a negative pregnancy test taken within the last 3 days.

My cancer is a type of stomach or GEJ cancer confirmed by lab tests.

Exclusion Criteria

My cancer got worse or I couldn't tolerate the treatment with specific immune therapy.

You are currently taking part in another study involving medication or have done so in the past 4 weeks.

I do not have severe nerve damage.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Immunotherapy

Induction Immunotherapy segment with pembrolizumab monotherapy every 3 weeks until irRECIST PD

Variable (until progression)

Every 3 weeks

Combination Therapy

Combination Therapy segment with pembrolizumab, ramucirumab, and paclitaxel

Variable (until progression)

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Paclitaxel (Anti-microtubule agent)
• Pembrolizumab (Monoclonal Antibodies)
• Ramucirumab (Monoclonal Antibodies)

Trial Overview The trial tests Pembrolizumab alone followed by combination therapy with Ramucirumab and Paclitaxel for advanced stomach cancers. Patients are randomly assigned to two groups receiving these treatments to compare effectiveness.

Participant Groups

Group I: Arm B Experimental Treatment 3 Interventions

Pembrolizumab will be administered every 3 weeks in combination with ramucirumab + paclitaxel. The paclitaxel schedule differs between the 2 arms.

Group II: Arm A Experimental Treatment 3 Interventions

Pembrolizumab will be administered every 3 weeks in combination with ramucirumab + paclitaxel. The paclitaxel schedule differs between the 2 arms.

Paclitaxel is already approved in Canada for the following indications:

Approved in Canada as Paclitaxel for:

• Ovarian cancer
• Breast cancer
• Non-small cell lung cancer
• Kaposi's sarcoma

Who Is Running the Clinical Trial?

Harry H Yoon

Lead Sponsor

Trials

1

Recruited

60+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Dr. Gianrico Farrugia

Mayo Clinic

Chief Executive Officer since 2019

MD from University of Malta Medical School

Dr. Richard Afable

Mayo Clinic

Chief Medical Officer

MD from Loyola Stritch School of Medicine

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a pilot study of 19 patients with metastatic gastroesophageal adenocarcinoma, all patients showed tumor size reduction after receiving ramucirumab and paclitaxel following immune checkpoint inhibition, despite 95% not responding to the initial treatment.

The combination of ramucirumab/paclitaxel after immune checkpoint inhibition resulted in significantly improved outcomes, with a higher objective response rate (58.8% vs 11.8%) and longer progression-free survival (12.2 months vs 3.0 months) compared to the last chemotherapy before immune checkpoint therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes on anti-VEGFR-2/paclitaxel treatment after progression on immune checkpoint inhibition in patients with metastatic gastroesophageal adenocarcinoma. Kankeu Fonkoua, LA., Chakrabarti, S., Sonbol, MB., et al.[2023]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

Biologic therapies, particularly those targeting HER2 and VEGF, are showing promise in treating esophageal and gastric cancers, with trastuzumab and ramucirumab currently recommended by the NCCN for specific patient groups.

Recent studies indicate that other agents like pertuzumab, apatinib, and pembrolizumab may improve overall and progression-free survival, suggesting a growing role for targeted biologic therapies in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. Samson, P., Lockhart, AC.[2020]

Ramucirumab significantly improves overall survival and progression-free survival in adults with advanced gastric or gastro-oesophageal junction adenocarcinoma, based on results from two phase III trials (REGARD and RAINBOW) involving patients treated with 8 mg/kg every 2 weeks.

The treatment is generally well-tolerated, with hypertension being the most common serious side effect, making ramucirumab a valuable second-line therapy option for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab: A Review in Advanced Gastric Cancer. Greig, SL., Keating, GM.[2023]

In a meta-analysis of 1231 patients, pembrolizumab and paclitaxel showed no significant difference in effectiveness for treating advanced gastroesophageal cancer, with similar objective response rates.

Both treatments can be considered viable options for patients, as they provide comparable time to response and similar rates of partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus paclitaxel for previously treated, advanced gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized clinical trials. Swed, S., Shaheen, N., Hafez, W., et al.[2022]

Ramucirumab is a fully human monoclonal antibody that targets and inhibits VEGFR-2, which plays a key role in cancer growth and progression.

It has received FDA approval as a monotherapy for advanced gastric cancer or gastro-oesophageal junction adenocarcinoma in patients who have not responded to previous chemotherapy, marking it as the first treatment approved for this specific condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab: first global approval. Poole, RM., Vaidya, A.[2023]

Ramucirumab significantly improved overall survival in patients with advanced gastric or gastroesophageal junction adenocarcinoma, both as a monotherapy (355 patients) and in combination with paclitaxel (665 patients), with hazard ratios of 0.78 and 0.81, respectively.

The most common side effects reported were hypertension and diarrhea for the monotherapy, and fatigue, neutropenia, diarrhea, and epistaxis for the combination therapy, indicating a manageable safety profile but with notable adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ramucirumab for Gastric Cancer. Casak, SJ., Fashoyin-Aje, I., Lemery, SJ., et al.[2023]

Ramucirumab is an effective treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma, approved for use as a second-line therapy based on studies showing it can prolong progression-free and overall survival.

While ramucirumab shows efficacy in treating these cancers, it is associated with an increased risk of adverse events such as fatigue, neutropenia, and nausea, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ramucirumab - a new anticancer agent]. Telekes, A., Deme, D.[2023]

The combination of nivolumab (an anti-PD-1 antibody) with irinotecan and a fluoropyrimidine showed a disease control rate of 73.3% in 15 patients with advanced unresectable gastroesophageal cancers, indicating potential efficacy in this challenging patient population.

The treatment was generally feasible, with a median progression-free survival of 7 months and overall survival of 13.3 months, although 33% of patients experienced dose delays or adjustments primarily due to fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in Combination with Irinotecan and 5-Fluorouracil (FOLFIRI) for Refractory Advanced Gastroesophageal Cancer. Rogers, JE., Xiao, L., Trail, A., et al.[2023]

In a phase II trial involving 111 patients with metastatic gastroesophageal adenocarcinoma, the combination of FOLFIRI and ramucirumab did not meet the primary endpoint of a 6-month overall survival rate of ≥65%, achieving only 54%.

While overall survival rates were similar between FOLFIRI plus ramucirumab and paclitaxel plus ramucirumab, FOLFIRI showed better objective response rates and progression-free survival, particularly in patients previously treated with docetaxel, suggesting potential for further investigation in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel - results from the phase II RAMIRIS Study of the German Gastric Cancer Study Group at AIO. Lorenzen, S., Thuss-Patience, P., Pauligk, C., et al.[2023]

Ramucirumab, a monoclonal antibody targeting VEGFR-2, has shown efficacy in treating advanced gastroesophageal cancer, both as a standalone treatment and in combination with paclitaxel, based on results from two large randomized trials (REGARD and RAINBOW).

The treatment with ramucirumab combined with paclitaxel was associated with increased rates of neutropenia and hypertension, which are common side effects of antiangiogenic therapies, and it has received FDA approval for patients who have progressed after prior chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab: targeting angiogenesis in the treatment of gastric cancer. Smyth, EC., Tarazona, N., Chau, I.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Outcomes on anti-VEGFR-2/paclitaxel treatment after progression on immune checkpoint inhibition in patients with metastatic gastroesophageal adenocarcinoma. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]

3. China pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. [2020]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Ramucirumab: A Review in Advanced Gastric Cancer. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus paclitaxel for previously treated, advanced gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized clinical trials. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Ramucirumab: first global approval. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ramucirumab for Gastric Cancer. [2023]

8. Hungary pubmed.ncbi.nlm.nih.gov

[Ramucirumab - a new anticancer agent]. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Nivolumab in Combination with Irinotecan and 5-Fluorouracil (FOLFIRI) for Refractory Advanced Gastroesophageal Cancer. [2023]

10. England pubmed.ncbi.nlm.nih.gov

FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel - results from the phase II RAMIRIS Study of the German Gastric Cancer Study Group at AIO. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Ramucirumab: targeting angiogenesis in the treatment of gastric cancer. [2023]