A Phase 1/2 Study of Combination Lorlatinib and Ramucirumab in Patients With Advanced ALK-rearranged Lung Cancers

Plain English Summary

A Study of Lorlatinib in Combination With Ramucirumab in People With Lung Cancer is a Phase 2 clinical trial sponsored by Memorial Sloan Kettering Cancer Center studying Non Small Cell Lung Cancer, Metastatic, Recurrent. This trial is testing a combination of two drugs, lorlatinib and ramucirumab, to see if they are safe and effective for treating advanced non-small cell lung cancer (NSCLC) with a specific genetic change (ALK-rearranged). It is for adults (over 18) with advanced or returning NSCLC that has an ALK gene fusion, and who have either not been treated with chemotherapy in the advanced stage or have previously been treated with certain other ALK-targeted drugs. Participants will receive lorlatinib by mouth and ramucirumab through an IV infusion. The study will determine the best dose of lorlatinib to use with ramucirumab. Alternative treatments for advanced ALK-positive NSCLC include other targeted therapies and chemotherapy, depending on prior treatments. The trial aims to enroll 56 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are 18 or older and have advanced or returning non-small cell lung cancer with a confirmed ALK gene fusion. You must have good organ function and a performance status that allows for treatment. You cannot join if you have previously received lorlatinib or ramucirumab, have unstable brain metastases, or have had recent major surgery or radiation. Women who are pregnant or breastfeeding cannot participate, and those who can become pregnant must use effective contraception. This trial is studying Non Small Cell Lung Cancer, Metastatic, Recurrent, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures will determine the highest dose of lorlatinib that can be safely given with ramucirumab (Phase 1) and how long patients live without their cancer getting worse (Progressio The specific primary outcome measures are: Maximum tolerated dose (MTD) (Phase I) (1 year); Progression-free survival (Phase II) (12 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a need for new treatment options for patients with ALK-rearranged lung cancer, particularly those who may have developed resistance to existing therapies. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Non Small Cell Lung Cancer, Metastatic, Recurrent, where improved treatment options are needed.

Investor Insight

This trial targets a specific subset of lung cancer patients, indicating a focus on precision medicine. Success could lead to a new combination therapy for a growing market of ALK-positive NSCLC patie Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of lorlatinib and ramucirumab, and how this combination might affect your current health. Participation involves regular clinic visits for drug administration, blood tests, and scans to monitor your cancer and any side effects. You will need to take lorlatinib daily by mouth and receive ramucirumab as an IV infusion every three weeks. This trial is currently recruiting participants. The trial is being conducted at 6 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 56 participants

Interventions

• DRUG: Lorlatinib — Lorlatinib 100 mg orally daily
• DRUG: Ramucirumab — Ramucirumab 10 mg/kg intravenous infusion once every three weeks is a tolerable and safe dose.

Primary Outcomes

• Maximum tolerated dose (MTD) (Phase I) (1 year)
• Progression-free survival (Phase II) (12 months)

Full Eligibility Criteria

Inclusion Criteria:

* Written informed consent
* Age \>18 years old
* Metastatic or recurrent, biopsy-proven non-small cell lung cancer
* ALK fusion identified by next generation sequencing (NGS) or IHC on material obtained from tumor or plasma
* Measurable (RECIST 1.1) indicator lesion not previously irradiated
* Karnofsky performance status (KPS) ≥ 70%
* Adequate organ function defined as follows: ANC ≥1.5 × 10\^9 /L, platelets ≥100 × 10\^9/L, hemoglobin ≥ 9 g/dL, INR ≤ 1.5, PTT or aPTT \<1.5x ULN, total bilirubin ≤ 1.5 × ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted), AST ≤ 3 × ULN, ALT ≤ 3 × ULN or ≤ 5 x ULN in the setting of liver metastases, Cr ≤1.5 ULN or CrCl ≥ 40 mL/min. If Cr is

  ≥ 1.5x ULN, a 24-hr urine collection to calculate creatinine clearance must be performed

  °The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (UA); if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate \<1000 mg of protein in 24 hours to allow participation in this protocol).
* Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin for a minimum of 14 days prior to trial enrollment without signs of active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor invading major vessels or known varices). Patients on warfarin must have an INR ≤ 3.0
* Patients must have recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5 Grade ≤1) from the acute effects of prior therapy, except for residual alopecia or peripheral neuropathy (up to grade 2 allowed)prior to start of therapy
* Patients in cohort 1 will be treatment-naïve in the metastatic setting. Prior treatment with adjuvant chemotherapy is allowed
* Patients in cohort 2 will have progressed or be intolerant of at least one second generation ALK TKI, including alectinib, brigatinib, or ceritinib.
* Patients may have received multiple ALK TKIs as well as chemotherapy, but one of these treatments must have been with a second-generation ALK TKI.
* Because the teratogenicity of ramucirumab is not known, the patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods).
* Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of protocol therapy.

Exclusion Criteria:

* Prior lorlatinib or ramucirumab exposure
* Symptomatic, unstable brain metastasis requiring therapy with steroids or radiation therapy. Patients with clinically stable brain metastases (previously treated or untreated) are eligible
* Women who are breastfeeding or pregnant
* Major radiotherapy within 2 weeks of starting treatment on protocol
* Major surgery within 4 weeks of starting treatment on protocol or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy
* Less than 3 weeks since previous chemotherapy, 4 weeks since immunotherapy, and 2 weeks from any investigational therapy
* Significant bleeding disorders or grade ≥3 bleeding episode within 12 weeks prior to enrollment. Patients with history of gross hemoptysis (defined as bright red blood of ≥1/2 teaspoon) within 8 weeks prior to enrollment will be excluded
* New or history of diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) or other significant thromboembolic event in the 12 weeks prior to first dose of protocol therapy. Patients with thromboembolic events diagnosed \>12 weeks prior to protocol therapy are eligible if on stable doses of anticoagulation as outlined above. Venous port or catheter thrombosis or superficial venous thrombosis are not considered significant events
* GI perforation and/or fistula or bowel obstruction within 6 months or risk factors for perforation prior to enrollment
* Child-Pugh B or greater cirrhosis or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
* Uncontrolled hypertension, defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg, prior to initiating study treatment, despite hypertensive intervention
* Serious or non-healing wound, ulcer or bone fracture within 28 days of enrollment
* Radiologically documented evidence of major blood vessel invasion or encasement by cancer or radiographic evidence of intratumor cavitation
* Active systemic bacterial infection (requiring intravenous \[IV\] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\]. Screening is not required for enrol

Trial Locations

• Memorial Sloan Kettering Monmouth (All Protocol Activities), Middletown, New Jersey, United States
• Memorial Sloan Kettering Bergen (All Protocol Activities), Montvale, New Jersey, United States
• Memorial Sloan Kettering Cancer Center Suffolk - Commack (All Protocol Activities), Commack, New York, United States
• Memorial Sloan Kettering West Harrison (All Protocol Activities), Harrison, New York, United States
• Memorial Sloan Kettering Cancer Center (All Protocol Activities), New York, New York, United States
• Memorial Sloan Kettering Nassau (All Protocol Activities), Rockville Centre, New York, United States

Frequently Asked Questions

Related Conditions

• Non-Small Cell Lung Cancer
• Metastatic Cancer
• Recurrent Cancer
• ALK-positive Lung Cancer
• Anaplastic Lymphoma Kinase (ALK) Rearrangement
• Tyrosine Kinase Inhibitors (TKIs)
• Targeted Cancer Therapy
• Oncology
• Thoracic Oncology
• Genomic Medicine

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