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A Study of Lorlatinib in Combination With Ramucirumab in People With Lung Cancer

Primary Purpose

Non Small Cell Lung Cancer, Metastatic, Recurrent

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lorlatinib
Ramucirumab
Sponsored by
Memorial Sloan Kettering Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non Small Cell Lung Cancer focused on measuring Lorlatinib, Ramucirumab, 23-131

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Memorial Sloan Kettering Monmouth (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Bergen (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Cancer Center Suffolk - Commack (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering West Harrison (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Cancer Center (All Protocol Activities)Recruiting
  • Memorial Sloan Kettering Nassau (All Protocol Activities)Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lorlatinib and ramucirumab

Arm Description

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.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD) (Phase I)
Dose limiting toxicities using the NCI Common Terminology Criteria for Adverse Events Version 5 (NCI-CTCAE) will be used to grade toxicities during the trial.
Progression-free survival (Phase II)
by RECIST

Secondary Outcome Measures

Full Information

First Posted
August 17, 2023
Last Updated
August 17, 2023
Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Eli Lilly and Company
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1. Study Identification

Unique Protocol Identification Number
NCT06007937
Brief Title
A Study of Lorlatinib in Combination With Ramucirumab in People With Lung Cancer
Official Title
A Phase 1/2 Study of Combination Lorlatinib and Ramucirumab in Patients With Advanced ALK-rearranged Lung Cancers
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 17, 2023 (Actual)
Primary Completion Date
August 17, 2028 (Anticipated)
Study Completion Date
August 17, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Eli Lilly and Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non Small Cell Lung Cancer, Metastatic, Recurrent
Keywords
Lorlatinib, Ramucirumab, 23-131

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
56 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Lorlatinib and ramucirumab
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lorlatinib
Intervention Description
Lorlatinib 100 mg orally daily
Intervention Type
Drug
Intervention Name(s)
Ramucirumab
Intervention Description
Ramucirumab 10 mg/kg intravenous infusion once every three weeks is a tolerable and safe dose.
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD) (Phase I)
Description
Dose limiting toxicities using the NCI Common Terminology Criteria for Adverse Events Version 5 (NCI-CTCAE) will be used to grade toxicities during the trial.
Time Frame
1 year
Title
Progression-free survival (Phase II)
Description
by RECIST
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gregory Riely, MD, PhD
Phone
646-608-3913
Email
rielyg@mskcc.org
First Name & Middle Initial & Last Name or Official Title & Degree
Alexander Drilon, MD
Phone
646-608-3758
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan Kettering Monmouth (All Protocol Activities)
City
Middletown
State/Province
New Jersey
ZIP/Postal Code
07748
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Phone
646-608-3913
Facility Name
Memorial Sloan Kettering Bergen (All Protocol Activities)
City
Montvale
State/Province
New Jersey
ZIP/Postal Code
07645
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Phone
646-608-3913
Facility Name
Memorial Sloan Kettering Cancer Center Suffolk - Commack (All Protocol Activities)
City
Commack
State/Province
New York
ZIP/Postal Code
11725
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Phone
646-608-3913
Facility Name
Memorial Sloan Kettering West Harrison (All Protocol Activities)
City
Harrison
State/Province
New York
ZIP/Postal Code
10604
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Phone
646-608-3913
Facility Name
Memorial Sloan Kettering Cancer Center (All Protocol Activities)
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Phone
646-608-3913
First Name & Middle Initial & Last Name & Degree
Alexander Drilon, MD
Phone
646-608-3758
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Facility Name
Memorial Sloan Kettering Nassau (All Protocol Activities)
City
Rockville Centre
State/Province
New York
ZIP/Postal Code
11570
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Riely, MD, PhD
Phone
646-608-3913

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.
Links:
URL
http://www.mskcc.org/mskcc/html/44.cfm
Description
Memorial Sloan Kettering Cancer Center

Learn more about this trial

A Study of Lorlatinib in Combination With Ramucirumab in People With Lung Cancer

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