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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I, Open-Label, Multicentre Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of AZD2811 in Patients With Advanced Solid Tumours.

Conditions
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Advanced Solid Tumours

Intervention / Treatment
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* Drug: AZD2811


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A Dose Escalation: 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. 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: Measurable or non-measurable (but evaluable disease) according to RECIST v1.1. Age ≥18 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 ECOG performance status 0-1. 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. Predicted life expectancy ≥12 weeks. 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. Sexually active males should be willing to use barrier contraception (i.e., condoms). Exclusion Criteria: 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. 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. Previous treatment with alisertib. 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. 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). Patients with diarrhoea NCI CTCAE v4.03 Grade ≥2. 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. Any evidence of active infection, severe or uncontrolled systemic diseases including uncontrolled hypertension, active bleeding diatheses, hepatitis B, hepatitis C and human immunodeficiency virus. 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. Treatment with haematopoietic colony-stimulating factors (e.g., G-CSF) ≤2 weeks prior to screening visit. 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. Lactating, breastfeeding, or positive pregnancy test for female patients of child-bearing potential. Concurrent conditions that in the Investigator's opinion would jeopardize compliance with the protocol. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>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<br>* 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.<br>|
| Experimental: Part B<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of dose-limiting toxicites (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: Grade 4 neutropenia for > 7 days, or febrile neutropenia. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding. 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. 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. Inability to receive all doses in Cycle 1 due to treatment-related toxicity. 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. | Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of Dose Limiting Toxicities (DLTs). | 
| 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. | Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of adverse events | 
| 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. | Patients will be followed for either 21 or 28 days in Cycle 1 to determine the incidence of abnormal laboratory results. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of encapsulated AZD2811, released AZD2811, and AZD2811 metabolites | PK parameters will be derived by non-compartment analysis. | 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. | 
| Time to maximum plasma concentration (tmax) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. | PK parameters will be derived by non-compartment analysis. | 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. | 
| 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. | PK parameters will be derived by non-compartment analysis. | 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. | 
| Area under the plasma concentration-time curve from zero extrapolated to infinity [AUC(0-inf)] for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. | PK parameters will be derived by non-compartment analysis. | 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. | 
| Terminal rate constant (λz) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. | PK parameters will be derived by non-compartment analysis. | 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. | 
| Terminal elimination half-life for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. | PK parameters will be derived by non-compartment analysis. | 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. | 
| Volume of distribution (Vz) for encapsulated AZD2811, released AZD2811, and AZD2811 metabolites. | PK parameters will be derived by non-compartment analysis. | 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. | 
| Objective Response Rate (ORR), including the number of complete and partial responses | 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. | Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter | 
| The incidence of Stable Disease (SD) | 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. | Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter | 
| The incidence of Progressive Disease (PD) | 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. | Patients will be assessed after every two treatment cycles (6 or 8 weeks) for up to 1 year and every 12 weeks thereafter | 
| The proportion of patients surviving at 6 months will assessed in Part B. |  | Survival will be determined at 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD2811, Advanced solid tumours, Small-cell lung cancer