Patient case: 32-year-old female with inflammatory myofibroblastic tumor; genetic feature: RANBP2-ALK fusion

Clinical trial: BATTLE-2 Program - A Biomarker-Integrated Targeted Therapy in Non-Small Cell Lung Cancer (NSCLC)

Summary: There are 2 parts in this study.
  The goal of Part 1 of this clinical research study is to find the highest tolerable dose of trametinib when given with pembrolizumab to patients with refractory (has come back after treatment) non-small cell lung cancer (NSCLC).
  The goal of Part 2 of this clinical research study is to learn if pembrolizumab given alone or in combination with trametinib at the dose that was found in Part 1 of the study can help to control NSCLC in patients who previously received chemotherapy or immunotherapy.
  The safety of the study drugs will be studied in both parts.
  This is an investigational study. Pembrolizumab is FDA approved and commercially available for treatment of many types of cancers, including NSCLC. Trametinib is FDA approved and commercially for the treatment of melanoma. It is considered investigational to use the study drug(s) to treat the type of NSCLC you have.
  Up to 217 participants will be enrolled in this multicenter study. Up to 150 will take part at MD Anderson.

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 2 groups of 3-6 participants will be enrolled in Part 1 of the study, and up to 190 participants will be enrolled in Part 2.
  If you are enrolled in Part 1, you will receive trametinib and pembrolizumab. The dose of trametinib you receive will depend on when you join this study. Your study doctor will tell you more about it.
  If you are enrolled in Part 2, you will be assigned to 1 of 3 study groups based on your previous therapy history:
  -  If you have not previously received immunotherapy, you will be randomly assigned (as in the flip of a coin) to receive either pembrolizumab alone (Group 1, monotherapy) or trametinib and pembrolizumab (Group 2, combination therapy). You will have an equal chance (50/50) of being assigned to either group.
  -  If you have previously received immunotherapy, you will receive trametinib and pembrolizumab (Group 3, combination therapy).
  The study doctor will tell you what study drug(s) you are receiving.
  All participants will receive the same dose of pembrolizumab.
  Study Drug Administration:
  Each cycle is 21 days.
  If you are in Part 1 or if you are in Groups 2 or 3 of Part 2, you will take trametinib by mouth 1 time each day for 14 days before Cycle 1. This is called the Run-In Period. After that, you will take trametinib during Days 1-10 of all cycles. You will not take any study drug during Days 11-21.
  Trametinib should be taken with a full glass of water (about 8 ounces) at least 1 hour before or 2 hours after a meal. If you vomit after taking trametinib, you should not retake the dose. Wait and take the next dose as scheduled.
  If a dose of trametinib is missed, that dose can be taken if it is more than 12 hours until the next scheduled dose. Otherwise, wait and take the next dose as scheduled.
  You will receive a study diary that has instructions on how to take the study drug. In this diary, you should record what times you take the study drug and if you missed any doses or vomited after taking the drug. You should bring the diary to each clinic visit.
  You will also receive pembrolizumab by vein over about 30 minutes on Day 1 of Cycles 2 and beyond. You will not receive pembrolizumab during Cycle 1.
  Length of Study:
  You may take the study drugs for up to 2 years. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Your participation in this study will be over after 3 years of follow-up (described below).
  Retreatment:
  If the disease appears to be getting worse or the tumors appear to be getting larger, you may still be able to receive the study drug(s) if you and your doctor decide it is in your best interest. Sometimes the disease appears to get worse but the study drug(s) are actually working.
  However, there are risks of continuing to receive the study drug(s) because the disease may actually be getting worse. You are still at risk for side effects due to the study drug(s). This could also delay starting other treatments. The disease may get worse to the point that you are no longer able to receive other treatments.
  If you choose to receive the study drug(s) after the disease gets worse, you will continue to have study visits as described below. The study doctor will discuss this option with you.
  Study Visits:
  It is possible that these visits may happen up to 7 days earlier or later than scheduled, if needed. At any time while you are on study, these tests/procedures may be repeated to check your health.
  Within 72 hours before your first dose of study drug(s), if you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a pregnancy test.
  On Day 1 of the 14-day Run-in Period and then on Day 1 of each cycle (all participants):
  -  You will have a physical exam.
  -  Blood (about 3½ teaspoons) will be drawn for routine testing (Day 1 of Cycle 1, for Group 1 only). Every 3 cycles, this sample will be used to check your thyroid function.
  -  You will have an EKG (Run-in period and Cycle 3 only).
  -  If your doctor thinks you need it, you will have an eye exam.
  On Day 1 of Cycle 2 and then every 3 cycles after that, blood (up to 3 teaspoons) will be drawn for pharmacodynamic (PD) testing. PD testing measures how the level of study drug in your body may affect the disease. If the doctor thinks it is needed, this may be performed more often.
  On Day 1 of Cycle 3, if you are in Part 1 or if you are in Groups 2 or 3 of Part 2, you will have a MUGA scan (Cycle 3 only).
  On Day 11 of Cycle 1 (for Part 1 participants and Groups 2 and 3 only):
  -  Blood (about 3 teaspoons) will be drawn for routine tests.
  -  If you are in Part 1 of the study, you will have a tumor biopsy for PD testing.
  During Cycle 3 and every odd numbered cycle after that (Cycles 5, 7, 9, and so on), you will have imaging scans to check the status of the disease. If needed, you may have these scans performed more or less often.
  At about Day 21 of Cycle 2:
  -  You will have a tumor biopsy for PD testing. If you are in Part 1 of the study and had a biopsy at Day 11 of Cycle 1, you will not have this biopsy.
  -  You will have lung function tests. This testing may be performed more often, if the doctor thinks it is needed.
  Research Blood Testing:
  Blood (about ½ teaspoon) will be drawn for pharmacokinetic (PK) testing at the below time points based on which study drug(s) you are taking. PK testing measures the amount of study drug in the body at different time points.
  For trametinib:
  -  On Day 1 of Run-In period, before the study drug dose and then 3 times over the 8 hours after the dose.
  -  On Day 11 of Cycle 1, Day 21 of Cycle 2, and Day 1 of Cycle 4, before the dose.
  Blood (about ½ teaspoon) will be drawn for antibody testing within 24 hours before you receive pembrolizumab and at the same time PK blood samples are collected. In addition, blood will be drawn on Day 11 of Cycle 1, Day 1 of Cycle 4, and then every 12 cycles after that and at progression.
  End-of-Study Visit:
  Within 7 days after your last dose of study drug(s) or at any time you stop taking part in this study:
  -  You will have a physical exam.
  -  You will have an eye exam.
  -  Blood (about 3 teaspoons) and urine will be collected for routine tests. Part of this blood sample will be used for PD testing.
  -  You will have a chest x-ray, CT scan, and/or MRI.
  Follow-Up and Long-Term Follow-Up:
  About 30 days after your last dose of study drug(s), you may have an ECHO or MUGA scan and asked how you are doing. If you do not come to the clinic for an ECHO/MUGA scan, you will be called by a member of the study staff. This call should take about 5-10 minutes.
  If you stopped taking the study drug(s) for reasons other than the disease getting worse, you will have an MRI/CT scan every 9 weeks.
  You will be called every 3 months for up to 3 years and asked about any cancer treatments you may be receiving. This phone call should take about 10 minutes.

Eligibility: Inclusion Criteria:
  1. Histologically or cytologically confirmed diagnosis of metastatic or unresectable, locally advanced, recurrent NSCLC that has been previously treated (Subjects who have failed adjuvant or locally advanced therapy within 6 months are also eligible to participate in the study)
  2. The subject has biopsy accessible tumor and is willing to undergo biopsy prior to planned protocol treatment
  3. Confirmation of the presence or absence of EGFR mutations and ALK gene fusions prior to study enrollment in all subjects. Subjects with known EGFR sensitizing mutational status or ALK fusion must have been treated and progressed on EGFR TKIs or ALK-directed therapy, or with tumors harboring EGFR T790M mutation to have received and progressed on therapy directed at the T790M mutation (e.g. Osimertinib). Subjects with known ROS1 translocation must have been treated and progressed on ROS1-directed therapy.
  4. Measurable disease according to RECIST 1.1 and irRECIST. At least one lesion of at least 1.0 cm in the long-axis diameter for a non-lymph node or at least 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 and irRECIST using either CT or MRI. If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of at least 1.5 cm
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  6. Males or females aged at least 18 years (or any age greater than 18 years as determined by country legislation) at the time of informed consent
  7. Adequate organ function laboratory values, defined as: a. Absolute neutrophil count (ANC) >/= 1.5 x 10^9/L or at least 1500/mm3 or at least 1.5 x 10^9/L b. Platelet count at least 100,000/mm3 or at least 100 x 10^9/L c. Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline (blood transfusions, hematopoietic growth factors and hematinics are not allowed during the 7 days prior to screening to correct Hb values less than 9 g/dL) d. Serum creatinine </= 1.5 × ULN or >/= 60 mL/minute for subjects with creatinine levels > 1.5 × the institutional ULN e. Serum total bilirubin </= 1.5 × ULN or direct bilirubin </= ULN for subjects with total bilirubin levels > 1.5 × ULN
  8. Continued from #7: f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 2.5 × ULN except for subjects with liver mets for whom ALT and AST should be </= 5× ULN. g. International Normalized Ratio (INR) or prothrombin time (PT) </= 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants h. Activated PTT (aPTT) </= 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant
  9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female and male subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  10. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
  11. Patients must be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  12. Prior MEK inhibitor therapy is allowed
  13. Prior anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) is allowed in part 1 (phase 1b) and is required for phase 2 cohort B of the study.
  Exclusion Criteria:
  1. Subjects participating in or who have participated in a study of an investigational agent or is using an investigational device within 4 weeks of the first dose of study treatment or have received any anti-cancer therapy, platinum-based chemotherapy, targeted, biological (including humanized antibodies), investigational, immunotherapy, or hormonal agent, within 4 weeks of the first dose of study treatment
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  3. Has had prior monoclonal antibody therapy within 4 weeks prior to Study Day 1 or who has not recovered (i.e., </= Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier
  4. Had prior chemotherapy, targeted small molecule therapy within 4 weeks, or radiation therapy within 2 weeks prior to Study Day 1 or who has not recovered (i.e., </= Grade 1 or at baseline) from AEs due to a previously administered agent - Note: Subjects with </= Grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: If a subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Note:Patients who have received >30 Gy to the thorax must have completed this radiation 6 months prior to enrollment in the study.
  5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell and squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
  6. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment
  7. Has an active autoimmune disease that requires systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Subjects who require intermittent use of bronchodilators or local steroid injections are NOT excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjӧrgen's syndrome are NOT excluded from the study
  8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis, or has history of pneumonitis that required systemic corticosteroids for recovery
  9. Has an active infection requiring systemic therapy
  10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the study, or in the opinion of the investigator, is not in the best interest of the subject to participate
  11. Has known psychiatric or substance abuse disorders that could interfere with cooperation with the requirements of the protocol
  12. Is pregnant or breastfeeding, or expecting to become pregnant or father a child within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study drug
  13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) for the immunotherapy-naïve cohort only.
  14. Has a known history of HIV (HIV ½ antibodies)
  15. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C [e.g., HCV RNA (qualitative)] is detected
  16. Has received a live vaccine within 30 days prior to the first dose of study drug
  17. History or current evidence/risk of RVO
  18. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval if that treatment cannot be either discontinued or switched to a different medication (not known to affect QT interval) prior to C1D1.
  19. Any of the following cardiac abnormalities or history: a) Clinically significant abnormal 12-lead ECG, QT interval (QTCB) > 480 ms, b) Inability to measure QT interval on ECG, c) Personal or family history of long QT syndrome, d) Implantable pacemaker or implantable cardioverter defibrillator, e) Resting bradycardia < 55 beats/min, f) History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for >30 days prior to randomization are eligible, g) History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting, within 6 months prior to randomization, h) History or evidence of current >/= Class II congestive heart failure as defined by NYHA, i) Treatment refractory hypertension defined as a blood pressure of systolic > 140 mm Hg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy, j) Cardiac metastases

Relevance to patient case: not relevant