Clinical Trials /

Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell Lung Cancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity

NCT01639508

Description:

The purpose of this phase II study is to find out what effects cabozantinib (XL184) has, good and/or bad, in patients whose tumors one of the following gene changes RET, ROS1, or NTRK fusion, or increased MET or AXL activity. A phase II study looks at how effective a medication is at treating a specific type of cancer and collects information on the side effects of the study treatment. RET, ROS1, or NTRK fusion or increased MET or AXL activity gene leads to lung cancer cell growth. Cabozantinib is an oral medicine that inhibits of RET, ROS1, NTRK, MET, and AXL. In addition, this drug interferes with other cell pathways that also cause cancer cells to grow, form new blood vessels, and spread to other organs of the body. The goal of using cabozantinib is to shrink the cancer and to prevent it from growing Cabozantinib has been studied and shown to cause cancer shrinkage in other cancers such as medullary thyroid cancer and prostate cancer. We thus have a good idea of what side-effects it causes and can anticipate them.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell Lung Cancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity
  • Official Title: A Phase II Study of Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell Lung Cancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity

Clinical Trial IDs

  • ORG STUDY ID: 12-097
  • NCT ID: NCT01639508

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
CabozantinibCabozantinib

Purpose

The purpose of this phase II study is to find out what effects cabozantinib (XL184) has, good and/or bad, in patients whose tumors one of the following gene changes RET, ROS1, or NTRK fusion, or increased MET or AXL activity. A phase II study looks at how effective a medication is at treating a specific type of cancer and collects information on the side effects of the study treatment. RET, ROS1, or NTRK fusion or increased MET or AXL activity gene leads to lung cancer cell growth. Cabozantinib is an oral medicine that inhibits of RET, ROS1, NTRK, MET, and AXL. In addition, this drug interferes with other cell pathways that also cause cancer cells to grow, form new blood vessels, and spread to other organs of the body. The goal of using cabozantinib is to shrink the cancer and to prevent it from growing Cabozantinib has been studied and shown to cause cancer shrinkage in other cancers such as medullary thyroid cancer and prostate cancer. We thus have a good idea of what side-effects it causes and can anticipate them.

Trial Arms

NameTypeDescriptionInterventions
CabozantinibExperimentalThis will be a single-institution, open label, two-stage, single agent trial of cabozantinib in patients with advanced NSCLCs.atients in GROUP A will have tumors with a RET fusion. Patients in GROUP B will have tumors with an NTRK fusion, or MET or AXL overexpression, amplication, or mutatation. Patients in GROUP C will have tumors with a ROS1 fusion.
  • Cabozantinib

Eligibility Criteria

        Inclusion Criteria:

        A subject must fully meet all of the following criteria to be eligible for the study:

          1. The subject has a pathologic diagnosis of non-small cell lung carcinoma that is
             metastatic or unresectable.

          2. Documented presence:

             Group A: KIF5B/RET or related variant RET fusions.

             Group B: any of the following aberrations

             ii. NTRK fusion iii. MET overexpression, amplification, or mutation iv. AXL
             overexpression, amplification, or mutation

             Group C: ROS1 infustion

          3. The subject is ≥ 18 years old on the day of consent.

          4. The subject has a Karnofsky performance status of > 70%.

          5. The subject has organ and marrow function and laboratory values as follows:

               1. Absolute neutrophil count (ANC) ≥ 1500/mm3 without colony stimulating factor
                  support

               2. Platelets ≥ 100,000/mm3 Hemoglobin ≥ 9 g/dL

               3. Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known
                  Gilbert's . disease, bilirubin ≤ 3.0 mg/dL

               4. Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 30 mL/min. For
                  creatinine clearance estimation, the Cockcroft and Gault equation should be used:

                  Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) Female:

                  Multiply above result by 0.85

               5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

                  ≤ 3.0 × ULN if no liver involvement, or ≤ 5 × ULN with liver involvement

               6. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (113.2 mg/mmol) creatinine or
                  24-hr urine protein of < 1 g

               7. Serum phosphorus, magnesium, and potassium ≥ LLN after adequate supplementation
                  if necessary

               8. The subject is capable of understanding and complying with the protocol
                  requirements and has signed the informed consent document. Sexually active
                  subjects (men and women) must agree to use medically accepted barrier methods of
                  contraception (eg, male or female condom) during the course of the study and for
                  4 months after the last dose of study drug(s), even if oral contraceptives are
                  also used. All subjects of reproductive potential must agree to use both a
                  barrier method and a second method of birth control. Women of childbearing
                  potential must have a negative pregnancy test at screening.

               9. Women of childbearing potential include women who have experienced menarche and
                  who have not undergone successful surgical sterilization (hysterectomy, bilateral
                  tubal ligation, or bilateral oophorectomy) or are not postmenopausal.

              10. Postmenopause is defined as amenorrhea ≥ 12 consecutive months. Note:

        women who have been amenorrheic for 12 or more months are still considered to be of
        childbearing potential if the amenorrhea is possibly due to prior chemotherapy,
        antiestrogens, ovarian suppression or any other reversible reason.

        Exclusion Criteria:

          1. Any type of systemic anticancer agent (including investigational) within 3 weeks of
             first dose of study treatment, or within 5 half-lives of the agent whichever is
             shorter. Subjects on LHRH or GnRH agonists may be maintained on these agents.

          2. Prior treatment with cabozantinib

          3. Radiation therapy for bone or brain metastasis within 2 weeks, any other external
             radiation therapy within 4 weeks of first dose of study drug. Systemic treatment with
             radionuclides within 4weeks. Subjects with clinically relevant ongoing complications
             from prior radiation therapy are not eligible.

          4. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all
             prior therapies except alopecia and other non-clinically significant AEs.

          5. Known uncontrolled symptomatic brain metastases or cranial epidural disease; subjects
             previously treated and on stable dose of corticosteroids and/or anticonvulsants for
             >10 days, or not requiring such medications, are eligible. Baseline brain scans are
             not required to confirm eligibility.

             Radiation therapy for bone or brain metastases within 2 weeks before first dose of
             study drug; or any other external radiation therapy or systemic treatment with
             radionuclides within 4 weeks before first dose of study drug. Subjects with clinically
             relevant ongoing complications from prior radiation therapy are not eligible

          6. The subject requires concomitant treatment, in therapeutic doses, unless deemed
             clinically unsafe to discontinue, with anticoagulants such as warfarin or
             warfarin-related agents, unfractionated heparin, thrombin or Factor Xa inhibitors, or
             antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 100 mg/day), low-dose
             warfarin (≤ 1 mg/day) are permitted. Both prophylactic and/or treatment dose low
             molecular weight (fractionated) heparin (LMWH) are permitted and are the preferred
             agents to administer.

          7. The subject has experienced any of the following within 3 months before the first dose
             of study treatment:

               -  clinically-significant hematemesis or gastrointestinal bleeding

               -  Clinically-significant hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood c. any
                  other signs indicative of pulmonary hemorrhage

          8. The subject has radiographic evidence of cavitating pulmonary lesion(s)

          9. The subject has tumor in contact with invading major blood vessels

         10. The subject has any evidence of an endotracheal or endobronchial tumor within 28 days
             before the first dose of cabozantinib.

         11. The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

               -  Cardiovascular disorders including Congestive heart failure (CHF): New York Heart
                  Association (NYHA) Class III (moderate) or Class IV (severe) at the time of
                  screening

                    -  Concurrent uncontrolled hypertension defined as sustained BP ≥ 150 mm Hg
                       systolic, or ≥ 90 mm Hg diastolic despite optimal antihypertensive treatment
                       (Note: If there is any BP measurement that is performed within the screening
                       period that is < 150 mm Hg systolic and <90 mm Hg diastolic, then BP does
                       not meet definition of sustained.)

                       ---- Any congenital history of long QT syndrome.

                    -  Any of the following within 6 months before the first dose of study
                       treatment:

                         -  unstable angina pectoris

                         -  clinically-significant cardiac arrhythmias

                         -  stroke (including TIA, or other ischemic event) myocardial infarction

                         -  thromboembolic event requiring therapeutic anticoagulation except if
                            anticoagulation is as stipulated in Exclusion Criterium #6. (Note:
                            subjects with a venous filter (e.g. vena cava filter) are not eligible
                            for this study)

               -  Gastrointestinal disorders particularly those associated with a high risk of
                  perforation or fistula formation including:

                    -  Any of the following within 28 days before the first dose of study
                       treatmentF

                         -  intra-abdominal tumor/metastases invading GI mucosa (malignant
                            abdominal ascites does not constitute mucosal invasion)

                         -  active peptic ulcer disease,

                         -  inflammatory bowel disease (including ulcerative colitis and Crohn's
                            disease), diverticulitis, cholecystitis, symptomatic cholangitis or
                            appendicitis

                         -  malabsorption syndrome

                    -  Any of the following within 6 months before the first dose of study
                       treatment:

                         -  history of abdominal fistula

                         -  gastrointestinal perforation

                         -  bowel obstruction or gastric outlet obstruction

                         -  intra-abdominal abscess. Note: Complete resolution of an
                            intra-abdominal abscess must be confirmed prior to initiating treatment
                            with cabozantinib even if the abscess occurred more that 6 months ago.
                            GI surgery (particularly when associated with delayed or incomplete
                            healing) within 28 days. Note: Complete healing following abdominal
                            surgery must be confirmed prior to initiating treatment with
                            cabozantinib even if surgery occurred more that 28 days ago.

               -  Other disorders associated with a high risk of fistula formation including PEG
                  tube placement within 3 months before the first dose of study therapy or
                  concurrent evidence of intraluminal tumor involving the trachea and esophagus.

               -  Other clinically significant disorders such as:

                    -  active infection requiring systemic treatment within 28 days before the
                       first dose of study treatment

                    -  serious non-healing wound/ulcer/bone fracture within 28 days before the
                       first dose of study treatment

                    -  history of organ transplant

                    -  concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
                       before the first dose of study treatment

                    -  Major surgery (eg, thoracotomy, removal or biopsy of brain metastasis)
                       within 3 months before Week 1 Day 1. Complete wound healing from major
                       surgery must have occurred 1 month before Week 1 Day 1 and from minor
                       surgery (eg, simple excision, tooth extraction) at least 10 days before Week
                       1 Day 1. Subjects with clinically relevant ongoing complications from prior
                       surgery are not eligible.

                    -  history of major surgery as follows:

         12. The subject is unable to swallow tablets

         13. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >
             500 ms 14 days before Week 1 Day 1

         14. The subject is pregnant or breastfeeding.

         15. The subject has a previously identified allergy or hypersensitivity to components of
             the study treatment formulation.

         16. The subject is unable or unwilling to abide by the study protocol or cooperate fully
             with the investigator or designee.

         17. Uncontrolled concurrent malignancy that would limit assessment of efficacy of
             cabozantinib.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:objective response rate (ORR) (Group A)
Time Frame:12 weeks
Safety Issue:
Description:by RECIST v1.1 criteria to cabozantinib in patients with advanced NSCLC who have tested positive for RET Fusion

Secondary Outcome Measures

Measure:progression-free survival (PFS) (Group A)
Time Frame:3 years
Safety Issue:
Description:Progression-free (PFS) and overall survival (OS) will be calculated using Kaplan-Meyer estimators starting from the time of treatment initiation. For PFS, patients alive without evidence of progression at the end of the study will be censored at the time of the last available follow-up. For OS, patients alive at the end of the study will be censored at the time of the last available follow-up.
Measure:overall survival (OS) (Group A)
Time Frame:3 years
Safety Issue:
Description:Progression-free (PFS) and overall survival (OS) will be calculated using Kaplan-Meyer estimators starting from the time of treatment initiation. For PFS, patients alive without evidence of progression at the end of the study will be censored at the time of the last available follow-up. For OS, patients alive at the end of the study will be censored at the time of the last available follow-up.
Measure:safety (Both Group A, B & C)
Time Frame:3 years
Safety Issue:
Description:Observed toxicities will be individually tabulated according to CTCAE version 4.0 and summarized using descriptive statistics.
Measure:progression-free survival (PFS) (Group B & C)
Time Frame:3 years
Safety Issue:
Description:Progression-free (PFS) and overall survival (OS) will be calculated using Kaplan-Meyer estimators starting from the time of treatment initiation. For PFS, patients alive without evidence of progression at the end of the study will be censored at the time of the last available follow-up. For OS, patients alive at the end of the study will be censored at the time of the last available follow-up with advanced NSCLCs whose tumors test positive for a ROS1 or NTRK fusion or MET or AXL overexpression or amplification who were treated with cabozantinib.
Measure:overall survival (OS) (Group B & C)
Time Frame:3 years
Safety Issue:
Description:Progression-free (PFS) and overall survival (OS) will be calculated using Kaplan-Meyer estimators starting from the time of treatment initiation. For PFS, patients alive without evidence of progression at the end of the study will be censored at the time of the last available follow-up. For OS, patients alive at the end of the study will be censored at the time of the last available follow-up with advanced NSCLCs whose tumors test positive for a ROS1 or NTRK fusion or MET or AXL overexpression or amplification who were treated with cabozantinib.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Lung
  • XL184 (CABOZANTINIB)
  • KIF5B/RET Positive
  • RET Fusion Positive
  • 12-097
  • Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity

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