Patient case: 68-year-old male with non-small cell carcinoma; genetic feature: MET

Clinical trial: Trial of CRLX101, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer

Summary: Background: CRLX101 consists of a sugar molecule cyclodextrin linked to a chemotherapy drug called camptothecin. The combined molecule or nanoparticle drug conjugate travels through the blood. Once inside cancer cells, the chemotherapy drug is released from the molecule. Olaparib is a drug that may stop cancer cells from repairing the DNA damage caused by chemotherapy. Researchers want to see how safe it is to give CRLX101 and olaparib together and to see how well the combination treats a specific type of lung cancer called small cell lung cancer (SCLC).
  Objectives:
  To test the safety and maximum dose of CLRX101 and olaparib together. To test how well they treat small cell lung cancer.
  Eligibility:
  Adults 18 and older with small cell lung cancer.
  Design:
  Participants will be screened with standard cancer care tests.
  Participants will get the 2 study drugs in 28-day cycles. CRLX101 will be given every 2 weeks, through a small plastic tube in an arm vein. Olaparib will be taken by mouth twice a day most days. Participants will keep a pill diary.
  For Cycle 1, participants will have 3 visits. All other cycles will have 2 visits.
  At study visits, participants may have:
  Blood and hair samples taken
  History and Physical exam
  Questions about health and side effects
  Pregnancy test
  Optional tumor biopsy where a piece of tumor is removed by needle after numbing the skin. .
  CT scan
  Injection of CRLX101 (twice per cycle)
  <TAB>Olaparib prescription <TAB>
  Participants will have a follow-up visit 4 weeks after finish taking the drugs. They will have a physical exam and blood tests. They may have a tumor biopsy. The study team will call the patient every 3 months for follow up after completing the study treatment.

Detailed description: Background:
  -  Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.
  -  Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few months.
  -  The use of PARP inhibitors in combination with chemotherapy builds upon pre-clinical data in lung cancer and other cancers supporting the notion that PARP inhibitors potentiate the effect of DNA damaging therapies.
  -  Despite their highly synergistic activity in preclinical models, human studies combining PARP inhibitors and camptothecins have not translated into clinical benefit due to enhanced toxicity with the combination.
  -  One approach to improve ability to combine camptothecins with agents that sensitize their activity like PARP inhibitors is to use alternative formulations that minimize toxicity to the normal tissues.
  -  CRLX101 is a nanoparticle drug conjugate composed of 20 (S)-camptothecin (a potent and highly selective topoisomerase I inhibitor) conjugated to a linear, cyclodextrinpolyethylene glycol-based polymer.
  -  Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Olaparib has an established safety profile and it is under investigation in a number of different cancers.
  Objectives:
  -  Phase I: To determine the MTD/ recommended Phase 2 dose (RP2D) of CRLX101 in combination with olaparib in patients with refractory cancers
  -  Phase II: To determine the antitumor activity of olaparib plus CRLX101 with respect to progression free survival at 16 weeks separately in SCLC patients with resistant and sensitive relapse
  Eligibility:
  Phase I
  -  Male or female adult patients greater than or equal to 18 years of age
  -  Histologically or cytologically confirmed, advanced solid tumor that is refractory to standard therapy and/or for whom no further standard therapy is available
  -  ECOG Performance Status of 0, 1 or 2
  Phase II
  -  Male or female patients greater than or equal to 18 years old
  -  Have a pathologically (histology or cytology) confirmed diagnosis of SCLC
  -  Disease progression on or after at least one platinum-based standard chemotherapy regimen for either limited or extensive stage disease.
  -  Have measurable disease per RECIST 1.1
  -  ECOG performance status of 0, 1 or 2
  Design:
  -  Patients meeting eligibility criteria will receive CRLX101 (IV Q 2weeks) plus olaparib (PO BID days 3-13 and days 17-26 administered in 28 day cycles, until disease progression or development of intolerable side effects. The MTD of the combination will be used in Phase II.
  -  Blood, tumor and hair samples will be collected at multiple time points for PK, PD analyses. Tumor biopsies are optional and will be performed only in SCLC patients (in Phase I and II) at the following time points: pre-treatment, on cycle 1 day 4 and at disease progression.
  -  Toxicity will be graded according to CTCAE version 4.0.
  -  Tumor assessments will be made using CT scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to RECIST version 1.1.
  -  After discontinuation of study treatment, follow-up for survival will be carried out every 3 months.
  -  The maximum number of patients on the phase I portion of the trial is 30 and the two cohorts in phase II may accrue up to 20 evaluable patients each. Thus, the maximum number of evaluable patients who may enroll on this trial is 70. In order to allow for a small number of in-evaluable patients, the accrual ceiling will be set at 75.
  -  It is anticipated that approximately 1 to 2 patients per month may enroll onto this trial; the trial is expect to complete accrual in 3-4 years.

Eligibility: -  INCLUSION CRITERIA:
  Phase I:
  -  Patients must have advanced solid tumor that is resistant or refractory to standard therapy. Histologic or cytologic diagnosis should be confirmed in NCI Laboratory of Pathology.
  -  A minimum of 2 weeks will be required from any prior therapy, including chemotherapy, immunotherapy and/or radiation. In addition, recovery to Grade less than or equal to 1 from all reversible toxicities related to prior therapy is required at study entry.
  -  Patients do not need to have measurable disease to enroll on phase I.
  -  Age greater than or equal 18 years.
  -  ECOG performance status less than or equal to 2.
  -  Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids. Patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study. Use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed.
  -  Patients must have normal organ and marrow function 5 days prior to C1D1 as defined
  below:
  -  leukocytes greater than or equal to 3,000/mcL
  -  absolute neutrophil count >1,500/mcL without growth factor support
  -  platelets greater than or equal 100,000/mcL without growth factor
  support
  -  hemoglobin greater than or equal 9 g/dL and no blood transfusion within 4 weeks OR greater than 10 g/dL and no blood transfusion within 2 weeks.
  -  total bilirubin less than or equal 1.5 x ULN (unless Gilbert s Disease)
  -  AST(SGOT)/ALT(SGPT) less than or equal 2.5 X institutional upper limit of normal (less than or wqual to 5X ULN if liver mets)
  -  creatinine within normal institutional limits
  OR
  -  creatinine clearance greater than or equal 50 mL/min (calculated using the Cockroft- Gault formula) for patients with creatinine levels above institutional normal.
  -  No features suggestive of MDS/AML on peripheral blood smear
  -  The effects of CRLX101 and olaparib on the developing human fetus are unknown. For this reason and because these agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 120 days (both male and female) following last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Fertile females of childbearing potential are defined as women physically capable of becoming pregnant unless the female patient cannot have children because of surgery or other medical reasons (effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-menopausal is defined as:
  -  Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments,
  -  LH and FSH levels in the post menopausal range for women under 50,
  -  radiation-induced oophorectomy with last menses >1 year ago,
  -  chemotherapy-induced menopause with >1 year interval since last menses,
  -  or surgical sterilization (bilateral oophorectomy or hysterectomy).
  -  Negative urine pregnancy test less than or equal to 3 days prior to C1D1 (women of childbearing potential only)
  -  Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  Phase II:
  -  Age greater than or equal to18 years.
  -  Patients must have histologically or cytologically confirmed diagnosis of SCLC. Pathologic diagnosis must be confirmed in NCI Laboratory of Pathology.
  -  Have received and progressed during or after a platinum-based standard chemotherapy regimen for first line treatment of SCLC, either limited stage or extensive stage.
  -  Patients could have received any number of therapies for relapsed or progressive disease, including re-treatment with original frontline regimen. A minimum of 2 weeks will be required from any prior therapy, including chemotherapy, immunotherapy and/or radiation. In addition, recovery to Grade less than or equal to 1 from all reversible toxicities related to prior therapy is required at study entry. No previous irradiation to the site of measurable or evaluable disease, unless that site had subsequent evidence of progression.
  -  Patients must have measurable disease as per Response Evaluation Criteria in Solid Tumors, version (RECIST 1.1).
  -  Radiographic evidence of disease progression after initial therapy should have been documented.
  -  ECOG performance status less than or equal to 2.
  -  Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids. Patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study. Use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed.
  -  Patients must have normal organ and marrow function less than or equal to 5days prior to C1D1 as defined below:
  -  leukocytes greater than or equal to 3,000/mcL
  -  absolute neutrophil count greater than or equal to 1,500/mcL without growth factor support
  -  platelets greater than or equal to 100,000/mcL without growth factor
  support
  -  hemoglobin greater than or equal to 9 gr/dl and no blood transfusion within 4 weeks OR greater than 10 g/dL and no blood transusion within 2 weeks
  -  total bilirubin less than or equal to 1.5 x ULN (unless Gilbert s Disease)
  -  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal (less than or equal to 5X ULN if liver mets)
  -  creatinine within normal institutional limits
  OR
  -  creatinine clearance greater than or equal to 50 mL/min (calculated using the Cockroft- Gault formula) for patients with creatinine levels above institutional normal.
  -  No features suggestive of MDS/AML on peripheral blood smear
  -  The effects of CRLX101 and olaparib on the developing human fetus are unknown. For this reason and because these agents are known to be teratogenic, women of childbearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 120 days (both male and female) following last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Fertile females of childbearing potential are defined as women physically capable of becoming pregnant unless the female patient cannot have children because of surgery or other medical reasons (effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-menopausal is defined as:
  -  Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments,
  -  LH and FSH levels in the post menopausal range for women under 50,
  -  radiation-induced oophorectomy with last menses >1 year ago,
  -  chemotherapy-induced menopause with >1 year interval since last menses,
  -  or surgical sterilization (bilateral oophorectomy or hysterectomy).
  -  Negative urine pregnancy test less than or equal to 3 days prior to C1D1 (women of childbearing potential only).
  EXCLUSION CRITERIA:
  Phase I and II:
  -  Patients who are receiving any other investigational agents.
  -  Persistent toxicities (greater than or equal to CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy
  -  Patients with myelodysplastic syndrome/acute myeloid leukemia or pneumonitis: or baseline features suggestive of myelodysplastic syndrome or acute myelogenous leukemia on peripheral blood smear or bone marrow biopsy, if clinically indicated.
  -  Hypersensitivity to study therapies and its excipients
  -  Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
  -  History of allergic reactions attributed to compounds of similar chemical or biologic
  composition to CRLX101 and/or olaparib or other agents used in study.
  - Patients receiving any medications or substances that are strong and moderate inhibitors
  or inducers of CYP3A are ineligible.
  -  Pregnant women are excluded from this study because CRLX101 and/or olaparib are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CRLX101 and/or olaparib, breastfeeding should be discontinued if the mother is treated with CRLX101 and/or olaparib. These potential risks may also apply to other agents used in this study.
  -  HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with CRLX101 and/or olaparib. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  -  Prolongation of QT/QTc interval (QTc interval >500 msec) using the Fredericia method of QTc analysis or family history of long QT syndrome. If single reading is above these minimum ranges, then repeat test in triplicate and evaluate eligibility based on average value
  -  Any chronic or concurrent acute liver disease.
  -  Concurrent treatment with Coumadin. Use of low molecular weight heparin use is permitted.
  -  History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6 months prior to C1D1
  -  Uncontrolled concurrent disease or illness including but not limited to:
  -  symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia
  -  unstable or untreated cardiac conditions or ejection fraction of <50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
  -  uncontrolled diabetes mellitus
  -  psychiatric illness that would limit compliance with study requirements, as determined by the Investigator
  -  Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.

Relevance to patient case: not relevant