Clinical Trials /

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

NCT02769962

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Prostate Carcinoma
  • Small Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of CRLX101, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer
  • Official Title: A Phase I/II Trial of CRLX101, a Nanoparticle Camptothecin With Olaparib in Patients With Relapsed/Refractory Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 160107
  • SECONDARY ID: 16-C-0107
  • NCT ID: NCT02769962

Conditions

  • Small Cell Lung Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Small Cell Lung Cancer
  • Lung Cancer

Interventions

DrugSynonymsArms
CRLX101Phase I
olaparibPhase I

Purpose

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.

        -  Urothelial Carcinoma (UC) of the Bladder is the fourth most common malignancy in men and
           the ninth most common in women.

        -  Prostate cancer is the most common cancer among men in the United States. While prostate
           cancer is initially responsive to androgen deprivation therapy (ADT), the median
           duration of sensitivity is 24-36 months. Moreover, patients develop resistance to
           current treatment options.

        -  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 in SCLC patients with resistant or sensitive
           relapse

        -  Expansion Cohorts: To determine overall response rate of CRLX101 plus olaparib in

      patients with mCRPC and urothelial carcinoma

      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 and/or an immune-checkpoint inhibitor for either limited or extensive stage

      disease.

        -  Have measurable disease per RECIST 1.1

        -  ECOG performance status of 0, 1 or 2

      Phase II Expansion Cohorts:

      -Have a pathologically (histology or cytology) confirmed diagnosis of urothelial

      carcinoma or metastatic, progressive, castrate resistant prostate cancer (mCRPC)

      -Disease progression on or after at least one platinum-based standard chemotherapy

      regimen and/or an immune-checkpoint inhibitor (except prostate cohort)

        -  Have measurable disease per RECIST 1.1 (except prostate cohort)

        -  Prior treatment with enzalutamide and/or abiraterone (prostate cancer cohort only)

        -  Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l]) (Prostate

      cohort only)

      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.

        -  Patients in Phase II will receive, the RP2D at DL4R CRLX101 12mg/m2 and olaparib 250mg
           BID.

        -  Blood, tumor and hair samples will be collected at multiple time points for PK, PD
           analyses. Hair sample collection is optional. Tumor biopsies are optional for SCLC and
           UC patients and mandatory for mCRPC patients (only baseline biopsy is mandatory).

        -  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 (3 cycles for mCRPC) 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, the SCLC
           cohort in phase II may accrue up to 27 evaluable patients, urothelial carcinoma
           expansion cohort may accrue up to 34 patients and mCRPC may accrue up to 25 patients.
           Thus, the maximum number of evaluable patients who may enroll on this trial is 116. In
           order to allow for a small number of in-evaluable patients, the accrual ceiling will be
           set at 123.

        -  It is anticipated that approximately 1 to 2 patients per month may enroll onto this
           trial; the trial is expect to complete accrual in 6-8 years.
    

Trial Arms

NameTypeDescriptionInterventions
Phase IExperimentalCRLX101 + olaparib
  • CRLX101
  • olaparib
Phase IIExperimentalCRLX101 + olaparib at MTD/RP2D
  • CRLX101
  • olaparib

Eligibility Criteria

        -  INCLUSION CRITERIA:

        Phase I:

          -  Patients must have advanced solid tumor that is resistant or refractory to standard
             therapy.

          -  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 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 less than ULN OR

               -  creatinine clearance greater than or equal 51 mL/min (calculated using the
                  Cockroft- Gault formula) for patients with creatinine levels above institutional
                  normal.

          -  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.

        Inclusion Criteria Phase II - SCLC:

          -  Age greater than or equal to18 years.

          -  Patients must have histologically or cytologically confirmed diagnosis of SCLC from a
             CLIA-certified laboratory.

          -  Have received and progressed during or after a platinum-based standard chemotherapy
             regimen and/or an immune-checkpoint inhibitor.

          -  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 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 g/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 less than ULN OR

               -  creatinine clearance greater than or equal to 51 mL/min (calculated using the
                  Cockroft- Gault formula) for patients with creatinine levels above institutional
                  normal.

          -  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).

        INCLUSION CRITERIA FOR UROTHELIAL CARCINOMA EXPANSION COHORT:

          -  Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the
             bladder, urethra, ureter, or renal pelvis from a CLIA-certified laboratory, with
             measurable disease by RECIST including lymphadenopathy and visceral metastatic
             disease.

          -  Male or female patients greater than or equal to 18 years of age.

          -  Patient must have received at least one platinum based regimen of chemotherapy and/or
             an immune-checkpoint inhibitor if appropriate with progressive disease.

          -  Prior antiangiogenic therapy are permitted (2-week washout from therapy is required).

          -  Bisphosphonates and denosumab are permitted if on a stable dose for greater than equal
             to 4 weeks.

          -  ECOG 0 2

          -  Patients must have normal organ and marrow function 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 g/dL and no blood transfusion within 4 weeks OR
             hemoglobin >10 g/dL, and no blood transfusion within 2 weeks

          -  total bilirubin less than or equal to 1.5 x ULN (less than or equal to 3 (SqrRoot) ULN
             for subjects with 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 less than or equal to ULN OR

          -  creatinine clearance greater than or equal to 51 mL/min (calculated using the
             Cockroft-Gault formula) for patients with creatinine levels above institutional
             normal.

          -  PT/INR and aPTT within 1.25 X ULN institutional limits, except where a lupus
             anti-coagulant has been confirmed

          -  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).

          -  Patients must be able to tolerate oral medications and not have gastrointestinal
             illnesses that would preclude absorption of olaparib.

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Willingness to release archival tissue sample for research purposes, if available

        INCLUSION CRITERIA FOR mCRPC EXPANSION COHORT:

          -  Patients must have metastatic, progressive, castrate resistant prostate cancer
             (mCRPC).

          -  Documented histopathological confirmation of prostate cancer from a CLIA-certified
             laboratory.

          -  All patients must have at least one lesion deemed safe to biopsy and be willing to
             undergo a mandatory baseline biopsy.

          -  Patients must have received prior treatment with enzalutamide and/or abiraterone with
             the exception of patients who were treated with docetaxel and androgen deprivation
             therapy for metastatic castrate-sensitive prostate cancer and progressed on docetaxel
             treatment or who progress within one month of the last docetaxel dose.

          -  Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l])

          -  Patients must have undergone bilateral surgical castration or must agree to continue
             on GnRH agonists/antagonists for the duration of the study.

          -  ECOG performance status less than or equal to 2

          -  Patients must have adequate bone marrow, hepatic, and renal function with:

          -  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 g/dL and no blood transfusion within 4 weeks OR
             hemoglobin > 10g/dL, and no blood transfusion within 2 weeks

          -  total bilirubin less than or equal to 1.5 x ULN (less than or equal to 3 (SqrRoot) ULN
             for subjects with Gilbert s Disease)

          -  AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal (less than or equal to 5X
             ULN if liver mets)

          -  creatinine less than or equal to ULN OR

          -  creatinine clearance greater than or equal to 51 mL/min (calculated using the
             Cockroft-Gault formula) for patients with creatinine levels above institutional
             normal.

               -  Men must be at least 18 years of age.

               -  Patient must be capable of understanding and complying with protocol requirements
                  and is willing to give informed consent.

          -  Men treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study and for the duration of study participation and for 120 days after
             last dose of study drug. Sexually active subjects and their female partners must agree
             to use medically accepted barrier methods of contraception (e.g., male or female
             condom) during the course of the study and for 3 months after the last dose of study
             drug(s), even if oral contraceptives are also used. All subjects of reproductive
             potential must also agree to use both a barrier method and a second method of birth
             control during the course of the study and for 3 months after the last dose of study
             drug(s). Should a woman become pregnant or suspect she is pregnant while her partner
             is participating in this study, she should inform her treating physician im...
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Expansion: To determine overall response rate of CRLX101 plus olaparib in patients with mCRPC
Time Frame:12 weeks
Safety Issue:
Description:Determine if slightly more than 50% of patients may be identified as being without progression by 12 weeks.

Secondary Outcome Measures

Measure:Evaluate the pharmacokinetic profile of CRLX101 (both the total drug and released camptothecin) and olaparib in plasma
Time Frame:Cycles 1 and 6
Safety Issue:
Description:Drug levels in blood
Measure:Evaluate the pharmacodynamic (PD) activity of CRLX101 in blood,surrogate tissue and tumor biopsy specimens.
Time Frame:Baseline, Cycle 1, then every 2cycles, and at progression
Safety Issue:
Description:Drug levels in blood.
Measure:Determine the duration of response (DOR), overall survival (OS), andprogression-free survival (PFS) of the combination
Time Frame:Every 3 months post-treatment
Safety Issue:
Description:DOR is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. OS is determined from the start of treatment until death. PFS is defined as the duration of time from start of treatment to time of progression ordeath, whichever occurs first.
Measure:Explore further the safety of the combination table oftoxicities including type, severity, time of onset, time of resolution and probable association with study regimen
Time Frame:Start of treatment through 30 days post last dose
Safety Issue:
Description:List of adverse event frequency
Measure:To determine safety in patients on expansion cohorts: table of toxicities including type, severity, time of onset, time of resolution and probable association with study regimen
Time Frame:Start of treatment through 30 days post last dose
Safety Issue:
Description:List of adverse event frequency
Measure:To determine expansion-free survival (PFS) on expansion cohorts
Time Frame:Every 3 months post-treatment
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:To determine duration of response and PSA on mCRPC expansion cohort
Time Frame:Every 12 weeks until progression
Safety Issue:
Description:PSA levels in blood

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • PARP Inhibitor
  • Topoisomerase I (Top1)
  • Camptothecins
  • Nanoparticle Drug Conjugate
  • Solid Tumors

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