Testing a new drug combination for lung cancer treatment

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

This study is testing a new combination of two drugs, lorlatinib and ramucirumab, to see if it’s safe and effective for people with a specific type of lung cancer that has an ALK fusion.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 56 (estimated)
• Ages: 19 Years and up
• Sex: All
• Sponsor: Memorial Sloan Kettering Cancer Center (Academic / other)
• Drugs / interventions: ramucirumab, alectinib, brigatinib, ceritinib, lorlatinib, chemotherapy, immunotherapy, radiation
• Locations: 6 sites (Middletown, New Jersey and 5 other locations)
• Trial ID: NCT06007937 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety and tolerability of combining lorlatinib and ramucirumab in patients with metastatic or recurrent non-small cell lung cancer (NSCLC) that has an ALK fusion. Researchers will administer one or two different doses of lorlatinib alongside ramucirumab to identify the optimal dose with minimal side effects. Additionally, the study aims to explore genetic markers that may predict patient responses to this treatment combination. The findings could pave the way for future efficacy trials based on the identified safe dosage.

Who should consider this trial

Good fit: Ideal candidates include adults over 18 with biopsy-proven metastatic or recurrent non-small cell lung cancer and an identified ALK fusion.

Not a fit: Patients without ALK fusions or those with other types of lung cancer may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could provide a new therapeutic option for patients with ALK-rearranged metastatic NSCLC.

How similar studies have performed: Other studies have shown promise in combining targeted therapies for lung cancer, making this approach both relevant and potentially impactful.

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 enrollment.
* Arterial thrombotic event or arterial thromboembolic event, including myocardial infarction, unstable angina, congestive heart failure ≥ NYHA class III, cerebrovascular accident or transient ischemic attack, within 6 months prior to enrollment
* Planned elective or major surgery during the trial
* Chronic therapy with any of the following within 7 days of enrollment:

  * Antiplatelet agents (such as clopidogrel, ticlopidine, dipyridamole, or anagrelide)
  * Aspirin up to 325 mg/day is permitted
* Serious uncontrolled medical disorders or psychological conditions that would, in the opinion of the investigator, limit the patient's ability to complete the study or sign an informed consent document
* Patients with unavoidable strong CYP3A inducer or inhibitor use (see table 15.4 for list of agents)

Where this trial is running

Middletown, New Jersey and 5 other locations

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

Study contacts

• Principal investigator: Gregory Riely, MD, PhD — Memorial Sloan Kettering Cancer Center
• Study coordinator: Gregory Riely, MD, PhD

Conditions Non Small Cell Lung Cancer; Metastatic; Recurrent; Lorlatinib; Ramucirumab; 23-131