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A Phase I Study of Safety, Tolerability, and PK of AZD2811 in Patients With Advanced Solid Tumors.

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ClinicalTrials.gov Identifier: NCT02579226
Recruitment Status : Recruiting
First Posted : October 19, 2015
Last Update Posted : June 12, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This Phase I study is primarily designed to evaluate the safety and tolerability of AZD2811 at increasing doses in patients with advanced solid tumours and for whom no standard of care exists. The study will be conducted in two parts, a dose-escalation phase (Part A) and a dose expansion phase (Part B). During Part A, the dose-escalation phase, patient enrolment will proceed according to a 3+3 design where the maximum tolerated dose (MTD) or the recommended Phase II dose (RP2D) could be identified. The study will also characterize the pharmacokinetic (PK) profile of AZD2811 and will explore the potential biological activity by assessing anti-tumour activity in patients. Part B will further explore PK parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD2811 RP2D as monotherapy (Group 1) in patients with relapsed/refractory SCLC.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumours Drug: AZD2811 Phase 1

Detailed Description:

This is a first-time-in-patient (FTIP) study with the nanoparticle formulation of AZD2811 primarily designed to evaluate the safety and tolerability of AZD2811 at increasing doses in patients with advanced solid tumours and for whom no standard of care exists.

The study will be conducted in two parts: Part A dose-escalation and Part B dose-expansion. In Part A, the dose-escalation phase, patient enrolment has proceeded according to a 3+3 design in order to identify the maximum-tolerated dose (MTD) or recommended Phase 2 dose (RP2D). AZD2811 monotherapy has been administered IV to patients with advanced solid tumours on Days 1 and 4 of a 28-day cycle in 6 dose levels without any relevant toxicities in the first 5 patient cohorts. In Cohort 6 (200 mg), grade 4 asymptomatic neutropenia was observed, and a dose-limiting toxicity was observed in 1 patient of the 5 evaluable patients. In Cohort 7 AZD2811 (200 mg) was given on Day 1 only of a 28-day cycle; in Cohort 8 AZD2811 (200 mg) was given on Day 1 only of a 21-day cycle. In Cohort 9, the AZD2811 dose was escalated to 400 mg on Day 1 every 21 days.

The Safety Review Committee (SRC) will review the safety and tolerability of AZD2811 for each cohort and schedule to determine the next cohorts. The study will also characterize the pharmacokinetic (PK) profile of AZD2811 and will explore potential biological activity by assessing anti-tumour activity in patients.

Once the MTD is established, Part B the dose expansion phase will continue to explore PK parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD2811 RP2D as monotherapy in 21 patients with relapsed/refractory SCLC.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-Label, Multicentre Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of AZD2811 in Patients With Advanced Solid Tumours.
Actual Study Start Date : October 28, 2015
Estimated Primary Completion Date : March 4, 2020
Estimated Study Completion Date : March 4, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part A
Part A dose-escalation will evaluate the safety and tolerability of AZD2811 monotherapy at increasing doses in patients with advanced solid tumours. Patients will receive AZD2811 on Days 1 and 4 of a 28-day cycle or Day 1 only in cycles of either 21 or 28 days.
Drug: AZD2811
The study will be conducted in 2 parts, dose-escalation (A) and dose-expansion (B). All patients in both parts of the study with receive AZD2811.

Experimental: Part B
Part B will include patients with relapsed or refractory small-cell lung cancer (SCLC). Patients will receive AZD2811 monotherapy at the recommended Phase 2 dose (RP2D).
Drug: AZD2811
The study will be conducted in 2 parts, dose-escalation (A) and dose-expansion (B). All patients in both parts of the study with receive AZD2811.




Primary Outcome Measures :
  1. The incidence of dose-limiting toxicites (DLTs) [ Time Frame: Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of Dose Limiting Toxicities (DLTs). ]

    Maximum Tolerated Dose (MTD) will be determined in Part A of the study by assessing the incidence of Dose Limiting Toxicities (DLTs), adverse events, and abnormal laboratory results.

    DLT is defined as:

    1. Grade 4 neutropenia for > 7 days, or febrile neutropenia.
    2. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding.
    3. Concurrent Grade ≥3 total bilirubin, ALT or AST or alkaline phosphatase lasting > 48 hours, or any change in liver function test results consistent with Hy's Law.
    4. Grade ≥3 non-hematologic AE except: a) Grade 3 diarrhoea controlled within 4 days with standard supportive care, b) Grade 3 elevations in ALT/AST that return to meet initial eligibility criteria within 7 days of study drug interruption.
    5. Inability to receive all doses in Cycle 1 due to treatment-related toxicity.
    6. Non-haematologic toxicity of ≥ Grade 2 (at any time during treatment) that, in the judgment of the Investigator and the Medical Monitor, is dose limiting.

  2. The incidence of adverse events [ Time Frame: Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of adverse events ]

    Maximum Tolerated Dose (MTD) will be determined in Part A of the study by assessing the incidence of Dose Limiting Toxicities (DLTs), adverse events, and abnormal laboratory results.

    At least 3 evaluable patients will be enrolled at each dose level (3+3 design) and will be evaluated for 21 or 28 days before escalation to the next dose level can occur. If one patient experiences a DLT, an additional 3 patients will be treated with the same dose. Therefore, a maximum of up to 6 patients may be enrolled per dose level.


  3. The incidence of abnormal laboratory results [ Time Frame: Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of abnormal laboratory results. ]

    Maximum Tolerated Dose (MTD) will be determined in Part A of the study by assessing the incidence of Dose Limiting Toxicities (DLTs), adverse events, and abnormal laboratory results.

    At least 3 evaluable patients will be enrolled at each dose level (3+3 design) and will be evaluated for 21 or 28 days before escalation to the next dose level can occur. If one patient experiences a DLT, an additional 3 patients will be treated with the same dose. Therefore, a maximum of up to 6 patients may be enrolled per dose level.



Secondary Outcome Measures :
  1. Maximum plasma concentration (Cmax) of encapsulated AZD2811, released AZD2811, and AZD2811 metabolites [ Time Frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose, and Cycle 2/Day 1 pre-dose and 2 hr post dose. ]
    PK parameters will be derived by non-compartment analysis.

  2. Time to maximum plasma concentration (tmax) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. [ Time Frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose, and Cycle 2/Day 1 pre-dose and 2 hr post dose. ]
    PK parameters will be derived by non-compartment analysis.

  3. Area under the plasma concentration-time curve from zero to the last measurable concentration [AUC(0-t)] for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. [ Time Frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose. ]
    PK parameters will be derived by non-compartment analysis.

  4. Area under the plasma concentration-time curve from zero extrapolated to infinity [AUC(0-inf)] for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. [ Time Frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose. ]
    PK parameters will be derived by non-compartment analysis.

  5. Terminal rate constant (λz) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. [ Time Frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose. ]
    PK parameters will be derived by non-compartment analysis.

  6. Terminal elimination half-life for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. [ Time Frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose. ]
    PK parameters will be derived by non-compartment analysis.

  7. Volume of distribution (Vz) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. [ Time Frame: Blood will be taken from subjects in Part A Cycle 1/Day 1: pre-dose, 1, 2, 4, 6, 8, 24, and 48 hr post dose; and Day 4: pre-dose, 1, 2, 4, 6, 8, 24, 48, 96, 336, 360, and 504 hr post dose. ]
    PK parameters will be derived by non-compartment analysis.

  8. Objective Response Rate (ORR), including the number of complete and partial responses [ Time Frame: Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter ]
    Baseline tumour imaging studies [computerized tomography (CT)] scan of the chest and abdomen/pelvis) will be performed within 28 days prior to the first dose of study drug (AZD2811) and will be repeated at the completion of Cycle 2 (Week 6 or Week 8) according the RECIST v1.1.

  9. The incidence of Stable Disease (SD) [ Time Frame: Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter ]
    Baseline tumour imaging studies [computerized tomography (CT)] scan of the chest and abdomen/pelvis) will be performed within 28 days prior to the first dose of study drug (AZD2811) and will be repeated at the completion of Cycle 2 (Week 6 or Week 8) according the RECIST v1.1.

  10. The incidence of Progressive Disease (PD) [ Time Frame: Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter ]
    Baseline tumour imaging studies [computerized tomography (CT)] scan of the chest and abdomen/pelvis) will be performed within 28 days prior to the first dose of study drug (AZD2811) and will be repeated at the completion of Cycle 2 (Week 6 or Week 8) according the RECIST v1.1.

  11. The proportion of patients surviving at 6 months will assessed in Part B. [ Time Frame: Survival will be determined at 6 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Part A Dose Escalation:

  1. Histological or cytological confirmation of a solid tumour and disease progression despite standard therapy(ies), or they must be intolerant to standard therapy(ies), or no standard therapy exists.
  2. Patients must have received ≤3 prior chemotherapy regimens in the metastatic setting which may have included irinotecan.

Part B Dose Expansion:

1. Patients must have received at least 1 prior platinum-based systemic therapy but no more than 3 prior systemic regimens for relapsed and/or refractory SCLC.

Inclusion Criteria All Patients:

  1. Measurable or non-measurable (but evaluable disease) according to RECIST v1.1.
  2. Age ≥18
  3. Adequate organ system functions, as outlined by a) absolute neutrophil count (ANC) ≥1.5 X 10^9/L, b) platelets ≥100 X 10^9/L, c) hemoglobin ≥9 g/dL, d) PT/PTT/INR ≤1.5 x upper limit of normal (ULN), e) total bilirubin ≤1.5 mg/dL, f) ALT and AST ≤3.0 times the ULN if no liver involvement or ≤5 times the ULN with liver involvement, g) creatinine ≤1.5 x ULN, OR calculated or measured creatinine clearance ≥50 mL/min, OR 24-hour measured urine creatinine clearance ≥50 mL/min
  4. ECOG performance status 0-1.
  5. Must provide an archived tissue sample for correlative testing, if available. If archived tissue is not available, patient will still be eligible for enrolment into the study.
  6. Predicted life expectancy ≥12 weeks.
  7. Females of child-bearing potential should be using adequate contraceptive measures from the time of screening until 6 months after study discontinuation, should not be breast feeding and must have a negative pregnancy test prior to start of dosing. Females of non-child-bearing potential must have evidence by the following criteria at screening: a) post-menopausal defined as aged > 50 and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, b) documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation, c) women < 50 would be considered postmenopausal if they have been amenorrhoeic for > 12 months following cessation of all exogenous hormonal treatments, and have serum follicle-stimulating hormone and luteinizing hormone levels in the postmenopausal range.
  8. Sexually active males should be willing to use barrier contraception (i.e., condoms).

Exclusion Criteria:

  1. Patients who have been treated with most recent radiotherapy, immunotherapy, chemotherapy or investigational drugs within ≤21 days or 5 half-lives (whichever is shorter) from enrolment (screening), and/or who have any unresolved NCI Common Terminology Criteria of Adverse Events (CTCAE) v4.03 > Grade 1 treatment-related side effect, with the exceptions of alopecia, should not be enrolled.
  2. Major surgery (excluding placement of vascular access) ≤21 days from beginning of the study drug or minor surgical procedures ≤7 days. No waiting is required following implantable port and catheter placement.
  3. Previous treatment with alisertib.
  4. Any of the following cardiac criteria: a) Congestive heart failure (CHF) per New York Heart Association (NYHA) classification > Class II, b) Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, c) Unstable angina or new-onset angina, d) QTcF interval >470 ms on screening ECG.
  5. Active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis, but excluding stable plaque psoriasis from the definition of active disease).
  6. Patients with diarrhoea NCI CTCAE v4.03 Grade ≥2.
  7. Patient has had prescription or non-prescription drugs or other products known to be strong inhibitors/inducers of CYP3A4 which cannot be discontinued prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug.
  8. Any evidence of active infection, severe or uncontrolled systemic diseases including uncontrolled hypertension, active bleeding diatheses, hepatitis B, hepatitis C and human immunodeficiency virus.
  9. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 3 weeks previously and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.
  10. Treatment with haematopoietic colony-stimulating factors (e.g., G-CSF) ≤2 weeks prior to screening visit.
  11. History of hypersensitivity to active or inactive excipients (e.g., PEG) of any drug in the study or drugs with similar chemical structure or class to those being investigated in the study.
  12. Lactating, breastfeeding, or positive pregnancy test for female patients of child-bearing potential.
  13. Concurrent conditions that in the Investigator's opinion would jeopardize compliance with the protocol.
  14. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

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): NCT02579226


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AstraZeneca Cancer Study Locator Service 1-877-400-4656 AstraZeneca@emergingmed.com

Locations
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United States, Alabama
Research Site Recruiting
Birmingham, Alabama, United States, 35294
United States, Colorado
Research Site Recruiting
Denver, Colorado, United States, 80218
United States, Florida
Research Site Recruiting
Sarasota, Florida, United States, 34232
United States, Massachusetts
Research Site Recruiting
Boston, Massachusetts, United States, 02215
United States, Michigan
Research Site Not yet recruiting
Detroit, Michigan, United States, 48201
United States, Missouri
Research Site Recruiting
Saint Louis, Missouri, United States, 63110
United States, Tennessee
Research Site Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Research Site Recruiting
Houston, Texas, United States, 77030
United States, Virginia
Research Site Not yet recruiting
Fairfax, Virginia, United States, 22031
United States, Wisconsin
Research Site Not yet recruiting
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Howard A. Burris, III, M.D. SCRI Development Innovations, LLC

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02579226     History of Changes
Other Study ID Numbers: D6130C00001
REFMAL 390 ( Other Identifier: SCRI Development Innovations, LLC )
First Posted: October 19, 2015    Key Record Dates
Last Update Posted: June 12, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by AstraZeneca:
AZD2811
Advanced solid tumours
Small-cell lung cancer

Additional relevant MeSH terms:
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Neoplasms