Immunotherapy + Anti-angiogenesis + Chemotherapy for Gastroesophageal Cancer

(SEQUEL Trial)

Recruiting at 1 trial location

Overseen By Ahran Lee

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

58 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for gastroesophageal cancer, which affects the stomach and esophagus. Participants will receive a mix of immunotherapy, anti-angiogenesis therapy (which stops tumor blood vessel growth), and chemotherapy. Researchers aim to determine if this combination can more effectively manage or shrink tumors. Individuals with metastatic or advanced gastroesophageal cancer who have previously tried anti-PD-1 therapy might be suitable candidates. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of pembrolizumab, ramucirumab, and paclitaxel is generally well-tolerated, meaning most people can handle it without serious problems. One study found that this combination did not cause any unexpected side effects, suggesting it is safe to use. Pembrolizumab, when compared to chemotherapy for advanced gastroesophageal cancer, proved just as effective in helping patients live longer, making it a reliable choice. The use of paclitaxel and ramucirumab together as a second treatment option has been linked to better health outcomes. Overall, this mix of treatments appears safe, with manageable side effects, according to existing research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining immunotherapy, anti-angiogenesis, and chemotherapy for gastroesophageal cancer because it offers a fresh approach to treatment. Unlike traditional chemotherapy alone, this combination uses Pembrolizumab, an immunotherapy drug, to help the body's immune system better recognize and attack cancer cells. Ramucirumab, an anti-angiogenesis agent, works by cutting off the blood supply that tumors need to grow. This multi-faceted attack could lead to improved outcomes, potentially enhancing the effectiveness of existing treatments and offering new hope for patients.

What evidence suggests that this trial's treatments could be effective for gastroesophageal cancer?

Research shows that using pembrolizumab, ramucirumab, and paclitaxel together may help treat gastroesophageal cancer. This trial will test two different schedules of paclitaxel combined with pembrolizumab and ramucirumab. Studies have found that this combination is generally well tolerated by patients and has led to promising survival outcomes. Specifically, pembrolizumab, when used instead of paclitaxel alone, has helped patients with advanced gastric cancer live longer, especially those with specific biomarkers. Additionally, the combination of paclitaxel and ramucirumab has successfully treated advanced gastric cancer. Together, these treatments offer a new and hopeful approach for patients facing this difficult condition. ^{1 2 4 6 7}

Who Is on the Research Team?

Harry H Yoon, MD, MHS

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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

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

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

I do not have severe nerve damage.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Paclitaxel
• Pembrolizumab
• Ramucirumab

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Taxol for:

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

Approved in European Union as Taxol for:

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

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+

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

Published Research Related to This Trial

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]

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]

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 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]

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 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]

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]

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, 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7602637/

Ramucirumab in Combination with Pembrolizumab ... Our results showed that this combination was well tolerated with no unexpected toxicities, and promising durable survival results.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9726310/

Pembrolizumab versus paclitaxel for previously treated ... This paper aims to compare the effectiveness and safety of pembrolizumab and paclitaxel as a second line for patients with locally advanced gastroesophageal ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2949819824000347

Real-world efficacy and toxicity data of paclitaxel and ... Paclitaxel/ramucirumab is an effective treatment in patients with advanced gastric cancer. •. The superiority of this regimen over alternative therapeutic ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02370498?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BConditionSearch%5D(%22Gastric%20Adenocarcinoma%22)%20AND%20AREA%5BInterventionSearch%5D(%22Pembrolizumab%22)))&rank=7&tab=results

A Study of Pembrolizumab (MK-3475) Versus Paclitaxel for ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

5. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2769922

Efficacy and Safety of Pembrolizumab or ... Pembrolizumab was noninferior to chemotherapy for overall survival in patients with advanced G/GEJ cancer with PD-L1 CPS of 1 or greater.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02370498

NCT02370498 | A Study of Pembrolizumab (MK-3475 ... This is a study for participants with advanced gastric or gastroesophageal junction adenocarcinoma who have had tumor progression after first-line treatment.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8732941/

2-year update of the randomized phase 3 KEYNOTE-061 trial Pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer.