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}

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 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Memorial Sloan Kettering Cancer Center (All Protocol Activities) New York, NY

Memorial Sloan Kettering Monmouth (All Protocol Activities) Middletown, NJ

Memorial Sloan Kettering Bergen (All Protocol Activities) Montvale, NJ

Memorial Sloan Kettering Cancer Center Suffolk - Commack (All Protocol Activities) Commack, NY

More Trial Locations

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center Lead Sponsor

Eli Lilly and Company Industry Sponsor

References

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

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. [2023] To explore the safety of osimertinib plus ramucirumab in patients with EGFR-mutated lung adenocarcinoma.

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] Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti-PD-L1 IgG1, in previously treated patients with advanced non-small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC).

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

Ramucirumab (Cyramza): A Breakthrough Treatment for Gastric Cancer. [2020] Ramucirumab (Cyramza): A breakthrough treatment for gastric cancer.

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

Clinical utility of ramucirumab in non-small-cell lung cancer. [2023] Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases and approximately 70% of patients with NSCLC have locally advanced or metastatic disease at presentation. In NSCLC patients with advanced or metastatic disease, second line treatment with chemotherapy is associated with a poor response rate. In this article, we have reviewed the role of ramucirumab in patients with NSCLC. Ramucirumab is not current standard of care in the first line setting in the treatment of advanced or metastatic NSCLC, based on phase II data which did not show any progression-free survival (PFS) and overall survival (OS) benefit when ramucirumab was compared with non-ramucirumab arm. The REVEL study was a phase III, placebo-controlled trial which included patients with stage IV NSCLC who had progressed during or after platinum-based chemotherapy, with or without bevacizumab. Median OS was 9.1 months vs 10.5 months (HR 0.86, 95% CI 0.75-0.98) in the placebo and ramucirumab group respectively. Seventy-nine percent of patients in ramucirumab arm and 71% of patients in non-ramucirumab arm had grade ≥3 treatment-related adverse events. The addition of ramucirumab to docetaxel can be considered in younger patients with good performance status as a second line treatment option. Additionally, combined blockage of the VEGFR and EGFR pathway has been utilized to overcome resistance to EGFR therapy. The RELAY trial was a phase III, placebo-controlled trial which included patients with sensitizing EGFR mutation positive stage IV NSCLC. Patients were randomized to either ramucirumab plus erlotinib or erlotinib. The trial showed that the combination therapy showed superior PFS benefit.

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

Ramucirumab: first global approval. [2023] Ramucirumab (Cyramza™ [US]), a fully human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), has been developed by Eli Lilly (formerly ImClone Systems) for the treatment of cancer. Ramucirumab has received its first global approval in the US for use as monotherapy in the treatment of advanced or metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in patients who experience disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy. Ramucirumab is the first treatment to be approved by the US FDA for this setting. This article summarizes the milestones in the development of ramucirumab leading to this first approval for the treatment of gastric cancer and gastro-oesophageal junction adenocarcinoma.

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

Ramucirumab in the treatment of non-small cell lung cancer. [2023] Therapeutic options for treating Non-Small Cell Lung Cancer (NSCLC) have recently increased. Ramucirumab (Cyramza), an anti-angionenic agent was approved in 2014 for treatment of several malignancies, including second-line treatment of patients with NSCLC with disease progression on or after platinum-based chemotherapy. Areas covered: We performed a comprehensive search of the literature focused on clinical trials with use of ramucirumab, targeting its evolution in the treatment of NSCLC. This review summarizes the results regarding its safety and efficacy. Expert opinion: Angiogenesis has been widely recognized as a quintessential feature in cancer, intrinsically mediating tumor survival and progression. Ramucirumab, an anti-VEGFR2 agent, combined with docetaxel, was FDA-approved for NSCLC patients. Results from a phase III trial have demonstrated the usefulness of this combination, with benefits in progression free survival and overall survival for NSCLC patients. A greater magnitude of benefit is seen in patients with aggressive tumor behavior. Treatment with ramucirumab is generally tolerable, however, there is potential for severe toxicity. Adverse events reported with this combination include neutropenia, febrile neutropenia and hypertension. Also, there is the intrinsic risk of bleeding resulting from the mechanism of action. As such, adverse events should be identified timely, so drug-related complications can be prevented.

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

Ramucirumab: preclinical research and clinical development. [2023] Ramucirumab (IMC-1121B, LY3009806), a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer.