Lorlatinib + Ramucirumab for Lung Cancer

Recruiting in Palo Alto (17 mi)

+5 other locations

Overseen by Gregory Riely, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

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

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This study will test the safety of the combination of ramucirumab and lorlatinib. The researchers will test one or two different doses of lorlatinib in combination with ramucirumab to find the drug combination dose that causes few or mild side effects in participants. Once the researchers find this dose, they can test it in future participants to see if it is effective in treating their metastatic ALK-rearranged NSCLC. The researchers are also looking to see whether there are specific genes or DNA sequences associated with a response to treatment with lorlatinib and ramucirumab.

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.

What data supports the effectiveness of the drug combination Lorlatinib and Ramucirumab for lung cancer?

Research shows that Ramucirumab, when combined with other drugs, has shown some effectiveness in treating advanced non-small-cell lung cancer (NSCLC), improving survival in certain cases. Additionally, combining Ramucirumab with other targeted therapies has been used to overcome resistance in lung cancer treatments. ^{1 2 3 4 5}

Is the combination of Lorlatinib and Ramucirumab safe for humans?

Ramucirumab, used in combination with other drugs for lung cancer, is generally tolerable but can cause serious side effects like low white blood cell counts, fever, high blood pressure, and bleeding. It's important for these side effects to be monitored and managed by healthcare professionals. ^{1 3 5 6 7}

How is the drug combination of Lorlatinib and Ramucirumab unique for lung cancer treatment?

The combination of Lorlatinib and Ramucirumab for lung cancer is unique because it pairs Lorlatinib, a targeted therapy for specific genetic mutations in lung cancer, with Ramucirumab, an anti-angiogenic drug that blocks blood vessel growth in tumors. This combination aims to target cancer cells directly while also cutting off their blood supply, potentially offering a novel approach compared to standard treatments. ^{1 3 5 6 7}

Research Team

Gregory Riely, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Lorlatinib (ALK Inhibitor)
• Ramucirumab (Monoclonal Antibody)

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.

Participant Groups

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 Japan, Canada for the following indications:

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+

Lisa M. DeAngelis

Memorial Sloan Kettering Cancer Center

Chief Medical Officer since 2021

MD from Columbia University

Selwyn M. Vickers

Memorial Sloan Kettering Cancer Center

Chief Executive Officer since 2022

MD from Johns Hopkins University

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

Findings from Research

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 (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]

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 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]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. [2023]

2. England 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). [2023]

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

Ramucirumab (Cyramza): A Breakthrough Treatment for Gastric Cancer. [2020]

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

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

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

Ramucirumab: first global approval. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Ramucirumab in the treatment of non-small cell lung cancer. [2023]

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

Ramucirumab: preclinical research and clinical development. [2023]