Lorlatinib + Ramucirumab for Lung Cancer

Recruiting at 5 trial locations

Overseen By Alexander Drilon, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Second-generation ALK TKIs

Must not be taking: Lorlatinib, Ramucirumab, Antiplatelets, Strong CYP3A inducers

Disqualifiers: Brain metastasis, Bleeding disorders, Hypertension, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for certain types of lung cancer, specifically metastatic ALK-rearranged non-small cell lung cancer. The researchers aim to determine if combining lorlatinib (a targeted therapy) and ramucirumab (a monoclonal antibody) is safe and effective, while also identifying any genetic factors that might predict a positive response. Individuals with this type of lung cancer who have either not been treated yet or have not responded well to previous treatments might be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain medications like antiplatelet agents or strong CYP3A inducers or inhibitors within 7 days of enrollment. If you're on full-dose anticoagulation, you must be on a stable dose for at least 14 days before joining the trial.

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

Research has shown that lorlatinib has been promising in earlier studies. Patients with advanced lung cancer have used it, and the long-term safety results are encouraging. For example, one study found that most patients tolerated lorlatinib well, with a good survival rate over several years.

Ramucirumab has been used with other cancer treatments, and its safety is well-documented. Patients generally tolerate it well, although some may experience side effects like high blood pressure or tiredness.

The combination of lorlatinib and ramucirumab is still under study, particularly to determine the best dose with the fewest side effects. Early research suggests that most patients can manage the combination with mild to moderate side effects. This ongoing research aims to find a safe dose to help more people in the future. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Lorlatinib and Ramucirumab for lung cancer because it targets cancer cells in a unique way. Lorlatinib is a third-generation ALK inhibitor, specifically designed to overcome resistance to previous ALK-targeted therapies, which is a common issue with current treatments. Ramucirumab, on the other hand, is a monoclonal antibody that inhibits angiogenesis, the process by which tumors develop their own blood supply. This dual approach not only aims to halt tumor growth more effectively but also addresses treatment resistance, offering a potentially powerful new option for patients who have exhausted existing therapies.

What evidence suggests that the combination of lorlatinib and ramucirumab could be effective for lung cancer?

Research has shown that lorlatinib, when used alone, is very effective for patients with ALK-rearranged non-small cell lung cancer (NSCLC). One study found that 60% of patients did not experience cancer progression after five years, a significant outcome. Ramucirumab stops the growth of blood vessels in tumors, potentially enhancing the effectiveness of other cancer drugs. In this trial, participants will receive a combination of lorlatinib and ramucirumab, which might be more effective for advanced ALK-rearranged NSCLC than using either drug alone. This combination targets cancer cells more precisely, offering hope for better disease control. ^{1 2 3 6 7}

Who Is on the Research Team?

Gregory Riely, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with ALK-rearranged non-small cell lung cancer that's metastatic or recurrent. They must have specific gene fusions, measurable lesions not previously treated with radiation, and good organ function. Prior chemotherapy is okay if recovered from side effects (except mild neuropathy or hair loss). Participants need stable anticoagulation if applicable and can't be pregnant or breastfeeding. Those in cohort 2 must have tried a second-generation ALK inhibitor.

Inclusion Criteria

My lung cancer has spread or come back and is confirmed by a biopsy.

My cancer did not respond or I couldn't tolerate at least one specific lung cancer treatment.

My blood tests show my organs are functioning well.

Exclusion Criteria

I haven't taken certain blood thinners, except possibly aspirin, in the last week.

I have not had serious bleeding or coughed up a significant amount of blood recently.

It's been less than 3 weeks since my last chemotherapy, 4 weeks since my last immunotherapy, and 2 weeks since any experimental treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive lorlatinib 100 mg orally daily and ramucirumab 10 mg/kg intravenous infusion once every three weeks to assess safety and dose limiting toxicities

3 weeks

1 visit (in-person) every 3 weeks

Phase 2 Treatment

Participants receive the maximum tolerated dose determined in Phase 1 to assess effectiveness in treating metastatic ALK-rearranged NSCLC

12 months

1 visit (in-person) every 3 weeks, interval imaging every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lorlatinib
• Ramucirumab

Trial Overview

The study tests different doses of lorlatinib combined with ramucirumab to find the safest dose level for future trials on effectiveness against advanced lung cancer. It also explores genetic factors linked to treatment response.

How Is the Trial Designed?

Group I: Lorlatinib and ramucirumab Experimental Treatment 2 Interventions

The phase 1 safety portion of the study will assess whether a dose of lorlatinib 100 mg orally daily and ramucirumab 10 mg/kg intravenous infusion once every three weeks is a tolerable and safe dose. Six patients will be enrolled at this dose level and assessed for dose limiting toxicities (DLTs) for one full cycle (21 days). Once the phase 1 portion of the study is complete, patients will be enrolled in the phase 2 portion of the study, cohort expansion at the MTD. Patients will be enrolled in two patient cohorts: cohort 1, treatment-naïve and cohort 2, patients who have progressed on prior second-generation ALK TKI. A cycle will be 21 days in length. Response to therapy will initially be assessed by interval imaging every 2 cycles.

Lorlatinib is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Lorbrena for:

• Metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Approved in European Union as Lorbrena for:

• Advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Approved in Japan as Lorbrena for:

• Unresectable, advanced/recurrent non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Approved in Canada as Lorbrena for:

• Metastatic non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

Ramucirumab (Cyramza) is a significant advancement in the treatment of gastric cancer, targeting the vascular endothelial growth factor receptor 2 (VEGFR-2) to inhibit tumor blood supply.

Clinical studies have demonstrated that ramucirumab improves overall survival in patients with advanced gastric cancer, making it a crucial option for those with this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab (Cyramza): A Breakthrough Treatment for Gastric Cancer. Singh, AD., Parmar, S.[2020]

In a study involving six patients with EGFR-mutated lung adenocarcinoma, the combination of osimertinib and ramucirumab was found to be generally safe, with only one case of dose-limiting toxicity (grade 3 appetite loss) and no other severe adverse events reported.

Five out of six patients showed a partial response to the treatment, with a median progression-free survival of 9.2 months for those with the EGFR T790M mutation, suggesting promising efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. Akamatsu, H., Ozawa, Y., Oyanagi, J., et al.[2023]

Ramucirumab is a monoclonal antibody that effectively inhibits VEGFR-2, showing promise in treating various cancers, particularly advanced gastric cancer, for which it has received FDA approval as a single agent.

While ramucirumab has demonstrated efficacy in early studies for other cancers like metastatic breast cancer and non-small-cell lung cancer, its role in these areas remains uncertain and requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab: preclinical research and clinical development. Aprile, G., Rijavec, E., Fontanella, C., et al.[2023]

Ramucirumab, an anti-VEGFR2 agent, has been shown to improve progression-free and overall survival in patients with Non-Small Cell Lung Cancer (NSCLC) when combined with docetaxel, particularly benefiting those with more aggressive tumors.

While treatment with ramucirumab is generally tolerable, it carries risks of severe adverse effects such as neutropenia, febrile neutropenia, hypertension, and potential bleeding, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab in the treatment of non-small cell lung cancer. Arrieta, O., Zatarain-Barrón, ZL., Cardona, AF., et al.[2023]

Ramucirumab, when added to docetaxel, can be considered as a second-line treatment option for younger patients with advanced non-small-cell lung cancer (NSCLC), despite showing no overall survival benefit compared to placebo in earlier studies.

In patients with EGFR mutation-positive stage IV NSCLC, the combination of ramucirumab and erlotinib demonstrated superior progression-free survival compared to erlotinib alone, indicating a potential strategy to overcome resistance to EGFR therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility of ramucirumab in non-small-cell lung cancer. Uprety, D.[2023]

The combination of ramucirumab and durvalumab was found to have manageable safety, with grade ≥3 treatment-related adverse events occurring in 32.1% of NSCLC, 37.9% of gastric/GEJ, and 42.9% of HCC patients, indicating that while there are risks, they are within acceptable limits for further study.

The treatment showed preliminary efficacy with an objective response rate of 11% for NSCLC and HCC, and 21% for gastric/GEJ, with better outcomes observed in patients with high PD-L1 expression, suggesting that this combination may be particularly beneficial for certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ). Bang, YJ., Golan, T., Dahan, L., et al.[2023]

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]

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