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

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ClinicalTrials.gov Identifier: NCT02769962
Recruitment Status : Recruiting
First Posted : May 12, 2016
Last Update Posted : November 29, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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.


Condition or disease Intervention/treatment Phase
Solid Tumors Small Cell Lung Carcinoma Carcinoma, Non-Small-Cell Lung Lung Neoplasms Small Cell Lung Cancer Lung Cancer Drug: CRLX101 Drug: olaparib Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 138 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of CRLX101, a Nanoparticle Camptothecin With Olaparib in Patients With Relapsed/Refractory Small Cell Lung Cancer
Study Start Date : May 11, 2016
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : December 31, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Olaparib

Arm Intervention/treatment
Experimental: Phase I
CRLX101 + olaparib
Drug: CRLX101

CRLX101 IV Q 2weeks Day 1 and Day 15, administered in 28 day cycles, until disease progression or development of intolerable side effects

Plus olaparib (PO days 3-13* and days 17-26*) administered in 28 day cycle, until disease progression or development of intolerable side effects.

P1: Dose Escalation P2: RP2

(* On days 13 and 26, only one dose of olaparib will be administered in the morning)


Drug: olaparib

olaparib (PO days 3-13* and days 17-26* administered in 28 day cycles, until disease progression or development of intolerable side effects

Plus CRLX101 (IV Q 2weeks, Day 1 and Day 15) administered in 28 day cycles, until disease progression or development of intolerable side effects

P1: Dose Escalation P2: RP2D

(* On days 13 and 26, only one dose of olaparib will be administered in the morning)


Experimental: Phase II
CRLX101 + olaparib at MTD/RP2D
Drug: CRLX101

CRLX101 IV Q 2weeks Day 1 and Day 15, administered in 28 day cycles, until disease progression or development of intolerable side effects

Plus olaparib (PO days 3-13* and days 17-26*) administered in 28 day cycle, until disease progression or development of intolerable side effects.

P1: Dose Escalation P2: RP2

(* On days 13 and 26, only one dose of olaparib will be administered in the morning)


Drug: olaparib

olaparib (PO days 3-13* and days 17-26* administered in 28 day cycles, until disease progression or development of intolerable side effects

Plus CRLX101 (IV Q 2weeks, Day 1 and Day 15) administered in 28 day cycles, until disease progression or development of intolerable side effects

P1: Dose Escalation P2: RP2D

(* On days 13 and 26, only one dose of olaparib will be administered in the morning)





Primary Outcome Measures :
  1. Expansion: To determine overall response rate of CRLX101 plus olaparib in patients with mCRPC [ Time Frame: 12 weeks ]
    Determine if slightly more than 50% of patients may be identified as being without progression by 12 weeks.

  2. Expansion: To determine overall response rate of CRLX101 plus olaparib in patients with urothelial carcinoma [ Time Frame: 8 weeks ]
    Best response recorded from the start of the treatment until disease progression/recurrence.

  3. Phase I: Determine the MTD/RP2D of CRLX101 plus olaparib in patients with refractory cancers. [ Time Frame: 28 days ]
    Number of DLTs during the first cycle.

  4. Phase II Chemo Resistant: Determine the PFS rate in the combination of olaparib plus CRLX101 at 16 weeks in SCLCpatients with chemo resistant relapse. [ Time Frame: 16 weeks ]
    Determine if slightly more than 50% of patients may be identified as being without progression by 16 weeks

  5. Phase II Chemo Sensitive: Determine the PFS rate in thecombination of olaparib plus CRLX101 at 16 weeks in SCLCpatients with chemo sensitive relapse. [ Time Frame: 16 weeks ]
    Determine if slightly more than 50% of patients may be identified as being without progression by 16 weeks


Secondary Outcome Measures :
  1. Evaluate the pharmacokinetic profile of CRLX101 (both the total drug and released camptothecin) and olaparib in plasma [ Time Frame: Cycles 1 and 6 ]
    Drug levels in blood

  2. 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 ]
    Drug levels in blood.

  3. Determine the duration of response (DOR), overall survival (OS), andprogression-free survival (PFS) of the combination [ Time Frame: Every 3 months post-treatment ]
    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.

  4. 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 ]
    List of adverse event frequency

  5. 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 ]
    List of adverse event frequency

  6. To determine expansion-free survival (PFS) on expansion cohorts [ Time Frame: Every 3 months post-treatment ]
    PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

  7. To determine duration of response and PSA on mCRPC expansion cohort [ Time Frame: Every 12 weeks until progression ]
    PSA levels in blood



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Phase I:

  • Patients must have advanced solid tumor that is resistant or refractory to standard therap.
  • 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 50 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.

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 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 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:

(NotEqual)- leukocytes >3,000/mcL

(NotEqual)- absolute neutrophil count >1,500/mcL without growth factor support

(NotEqual)- platelets >100,000/mcL without growth factor support

(NotEqual)- hemoglobin greater than or equal to 10 g/dL in the absence of packed red blood cells transfusion 28 days prior to dosing OR

(NotEqual)- hemoglobin >9 g/dL, if the value is constant across 2 readings within 2 weeks in the absence of packed red blood cells transfusion 28 days prior to dosing

(NotEqual)- 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)

(NotEqual)- AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal (less than or equal to 5X ULN if liver mets)

(NotEqual)- creatinine less than or equal to ULN OR

(NotEqual)- creatinine clearance >51 mL/min (calculated using the Cockroft-Gault formula) for patients with creatinine levels above institutional normal.

(NotEqual)- 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:

(NotEqual)- leukocytes >3,000/mcL

(NotEqual)- absolute neutrophil count >1,500/mcL without growth factor support

(NotEqual)- platelets >100,000/mcL without growth factor support

(NotEqual)- hemoglobin greater than or equal to 9 g/dL

(NotEqual)- 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)

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

(NotEqual)- creatinine less than or equal to ULN OR

(NotEqual)- creatinine clearance >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...

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02769962


Contacts
Contact: Linda C Sciuto, R.N. (240) 760-6117 lsciuto@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02769962     History of Changes
Other Study ID Numbers: 160107
16-C-0107
First Posted: May 12, 2016    Key Record Dates
Last Update Posted: November 29, 2018
Last Verified: November 27, 2018

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

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
PARP Inhibitor
Topoisomerase I (Top1)
Camptothecins
Nanoparticle Drug Conjugate

Additional relevant MeSH terms:
Carcinoma
Lung Neoplasms
Small Cell Lung Carcinoma
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Olaparib
Camptothecin
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors