Adenocarcinoma of Lung, Locally Advanced Solid Tumor, Metastatic Cancer, Non-Small Cell Lung Cancer With EGFR Mutation
Conditions
Brief summary
This is a prospective, single arm, phase Ib/IIa study. Up to 25 patients will be enrolled into the study (Part A: 2-18; Part B: 7-19). The study has been designed to allow an investigation of the optimal combination dose and schedule whilst of Osimertinib plus Anlotinib in patients with EGFRm+, treatment-naïve IIIb/IV Non-Small Cell Lung Cancer (NSCLC) ensuring the safety of patients with intensive safety monitoring. There are two main parts to this study; Part A, Combination dose finding and Parts B, Dose expansion.
Detailed description
Part A has been designed to identify the recommended dose of the combination of Osimertinib plus Anlotinib for further clinical evaluation based upon assessment of the safety and tolerability data collected during the first 21 days (cycle 1, 21 days per cycle). A cycle of study treatment will be defined as 21 days. Dosing will begin at Osimertinib 80mg QD continuously and Anlotinib 8mg QD from day1 to 14 of a 21-day cycle. In the first 6 patients, a delay of at least 21 days (the first group of 3 patients) and a delay of at least 7 days (the second group of 3 patients) will be mandatory between the administration of the first dose to the first patient and administration of first dose to subsequent patients. Patients will be enrolled to ensure a minimum of 3 and a maximum of 6 evaluable patients per cohort. Dose escalation and de-escalation will follow the scheme below, according to the following logic：If no dose-limiting toxicity (DLT) is observed (for definition see Section 4.1.3) in a cohort of 3 evaluable patients then dose escalation may occur. Dose increases will be permitted after review of data from a minimum of 3 evaluable patients has been performed. * If one patient experiences a DLT in a group of 3 evaluable patients then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients then dose escalation may occur. * If 2 or more patients experience a DLT in a group of up to 6 patients, irrespective of the number of patients enrolled, the dose will be considered not tolerated and recruitment to the cohort and dose escalation will cease. Safety will be intensively monitored in part A. If RP2D was not reached in Part A, Part B would not be initiated. If RP2D was reached in Part A, eligible patients in part B will be enrolled and receive Osimertinib (80mg QD, continuously) plus Anlotinib (RP2D, QD from day 1 to 14 of a 21-day cycle) till disease progression (PD) or unacceptable toxicity, with the aim to further evaluate the safety, tolerability and efficacy in terms of ORR, DCR, DOR, PFS, overall survival at 12 months. For all eligible patients (Part A and Part B), tissue and/or blood samples at baseline and PD will be collected to understand the resistance profile.
Interventions
DRUGOsimertinib
Osimertinib, 80mg, QD, p.o.
DRUGAnlotinib
(Phase Ib) Anlotinib, from 8mg to10mg to 12mg, QD, p.o. from day 1 to 14 of a 21-day cycle. (Phase IIa)Anlotinib, given at RP2D dose QD, p.o. from day 1 to 14 of a 21-day cycle.
Sponsors
Shanghai Chest Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* For inclusion in the study subjects should fulfil the following criteria: 1. Provision of informed consent prior to any study specific procedures. 2. Aged at least 18 years. 3. Histologically or cytologically confirmed locally advanced/metastasis NSCLC, adenocarcinoma of the lung (AJCC Eighth Edition TNM Stage ⅢB to stage Ⅳ), not amenable to curative surgery or radiotherapy. 4. WHO/Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 with no deterioration over the previous 2 weeks and a minimum life expectation of at least 12 weeks. 5. The tumour harbours one of the most common EGFR mutations known to be associated with EGFR-TKI sensitivity (exon 19 deletion; L858R) either alone or in combination with other EGFR mutations as confirmed by a local test. 6. No prior systemic anti-cancer, EGFR-TKI, or immunotherapy therapy for their locally advanced or metastasis disease (biopsy will be at time of diagnosis of locally advanced/metastasis disease). 7. At least one lesion is measurable based on Response Evaluation Criteria in Solid Tumours (RECIST 1.1). 8. Adequate bone marrow reserve and organ function as follows: * Absolute neutrophils count (ANC) ≥1.5x109/L (band neutrophil and segmented neutrophil), platelets \>100x109/L and Hb ≥90g/L. * Hepatic: total bilirubin ≤1.5 times upper limit of normal (ULN). * Alkaline phosphatase, alanine transaminase (ALT) and aspartate transaminase (AST)≤3.0 ULN (or ≤5 ULN in case of known liver involvement). * Renal: Serum Creatinine ≤1.5ULN, creatinine clearance (CCr) ≥50mL/min 9. Female patients of childbearing potential must be using adequate contraceptive measures (see Restrictions, Section3.5), must not be breast feeding, and must have a negative pregnancy test prior of study treatments and confirmed prior to start of dosing on day 1. Otherwise, they must have evidence of non-childbearing potential as defined below: * Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments * Women under 50 years would be consider post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution * Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 10. Male patients must be willing to use barrier contraception, i.e., condoms (see Restrictions, Section 3.5) 11. Optional provision of an unstained, archived tumour tissue samples or fresh tissue and/or blood in a quantity sufficient to allow for central NGS testing (FFPE slices or fresh tumor tissue or blood at sufficient amount for NGS analysis).
Exclusion criteria
\- Subjects must not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose(RP2D) | Up to approximately 6 months | RP2D is defined as the dose cohort as follows: (1). If 2 or more of 6 patients in cohort 1 experienced a DLT, the combination would not be considered tolerable. There would be no RP2D and no dose expansion. (2). If none of the first 3 patients or 1 of 6 patients in starting dose cohort 1 experienced a DLT, dose escalation to cohort 2 would be done in the next 3 to 6 patients. If 2 or more patients experienced a DLT in up to 6 patients in cohort 2, the RP2D will defined as Osimertinib 80mg and Anlotinib 8mg. (3).If none of the first 3 patients or 1 of 6 patients in cohort 2 experienced a DLT, dose escalation to cohort 3 would be done in the next 3 to 6 patients. If 2 or more patients experience a DLT in up to 6 patients in cohort 3, the RP2D will defined as Osimertinib 80mg and Anlotinib 10mg. (4). If none of the first 3 patients or 1 out of 6 patients experienced a DLT in cohort 3, the RP2D would be Osimertinib 80mg and Anlotinib 12mg. |
| ORR according to RECIST Version 1.1 | Up to approximately 3 years following the first dose of study drug | According to RECIST 1.1, the proportion of subjects whose tumors were assessed as CR+PR by subcenter imaging evaluation was recorded from the time they were first treated until disease progression or initiation of a new anticancer treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of disease remission (DOR) | Up to approximately 3 years following the first dose of study drug | The time from objective tumor remission (CR or PR) to objective tumor progression or death for any reason (whichever occurs first) was recorded for the first time. |
| Dose-limiting toxicity (DLT) | occurs from the first dose of study drug (Day 1, Cycle 0) up to the last day of Cycle 1 (21 days after start of dosing) | A DLT is defined as any toxicity not attributable to the disease or disease-related processed under investigation. |
| Overall Survival(OS) | Up to approximately 5 years following the first dose of study drug | The time from the first use of the drug into the group to the time of all-cause death. For the subjects who were still alive at the last follow-up, the OS was deleted according to the time of the last follow-up. For the subjects who lost the follow-up, their OS was counted as data deletion according to the last confirmed survival time before the loss of follow-up. |
| Disease progression-free survival(PFS) | Up to approximately 3 years following the first dose of study drug | The time from the first use of the drug into the group to the progression of the disease or death (in terms of the first appearance) |
| Disease Control Rate (DCR) | Up to approximately 3 years following the first dose of study drug | Proportion of patients whose tumors shrink or remain stable for a certain period of time, including CR, PR, and SD; |
Countries
China
Outcome results
None listed