Advanced Lung Tumor Treated by Osimertinib Plus Anlotinib

NCT04770688 | Completed Phase 1

• 1 other identifier: ESR-18-13979
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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.

Conditions

Non-Small Cell Lung Cancer With EGFR Mutation; Locally Advanced Solid Tumor; Metastatic Cancer; Adenocarcinoma of Lung

Outcome Measures

Primary Outcomes (2)

• Recommended Phase II Dose(RP2D)

  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.

  Up to approximately 6 months

• ORR according to RECIST Version 1.1

  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.

  Up to approximately 3 years following the first dose of study drug

Secondary Outcomes (5)

• 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)

• Disease Control Rate (DCR)

  Up to approximately 3 years following the first dose of study drug

• Duration of disease remission (DOR)

  Up to approximately 3 years following the first dose of study drug

• Disease progression-free survival(PFS)

  Up to approximately 3 years following the first dose of study drug

• Overall Survival(OS)

  Up to approximately 5 years following the first dose of study drug

Study Arms (1)

Osimertinib + Anlotiib

EXPERIMENTAL

Escalating doses and expanding doses of Anlotinib administered with Osimertinib

Drug: Osimertinib; Drug: Anlotinib

Interventions

Osimertinib DRUG

Osimertinib, 80mg, QD, p.o.

Also known as: Tagrisso

Osimertinib + Anlotiib

Anlotinib DRUG

(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.

Also known as: Focus V

Osimertinib + Anlotiib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of informed consent prior to any study specific procedures.
• Aged at least 18 years.
• 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.
• 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.
• 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.
• 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).
• At least one lesion is measurable based on Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
• 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).

You may not qualify if:

• Patients with non-lung adenocarcinoma including lung squamous carcinoma, or mixed histology, etc.
• Treatment with any of the following:
• Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug.
• Patients currently receiving (or unable to stop use prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3-week prior) (Appendix B). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
• Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater.
• Any concurrent and/or other active malignancy that has required treatment within 5 years of first dose of study drug.
• Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than CTCAE grade 1 at the time of starting study drug with the exception of alopecia and grade 2, prior chemotherapy-induced neuropathy.
• Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, and have had a stable neurological status for at least 2 weeks after completion of definitive therapy. Patients may be on corticosteroids to control brain metastases if they have been on a stable dose for 2 weeks (14 days) prior to the start of study treatment and are clinically asymptomatic.
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• Recent active digestive disease such as duodenal ulcers, ulcerative colitis, ileus, ect., intestinal perforation, intestine fistula, or other conditions may lead to gastrointestinal bleeding or perforation which regimented at investigators' discretion.
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of Osimertinib and Anlotinib.
• Cardiac function evaluation: LVEF \<50%, a recent history of MI in 6 months, severe/unstable angina or coronary bypass surgery, or cardiac insufficiency ≥ NYHA 2. Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) \>470 msec.
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, interval \>250 msec.
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium \< LLN; Serum/plasma magnesium \< LLN; Serum/plasma calcium \< LLN), congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes.

Sponsors & Collaborators

• Shanghai Chest Hospital: lead

Study Sites (1)

Shanghai Chest hospital

Shanghai, Shanghai Municipality, 200030, China

Location

Related Publications (8)

• Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. doi: 10.1016/S1470-2045(14)70381-X. Epub 2014 Aug 27.

  PMID: 25175099 RESULT

• Ichihara E, Hotta K, Nogami N, Kuyama S, Kishino D, Fujii M, Kozuki T, Tabata M, Harada D, Chikamori K, Aoe K, Ueoka H, Hosokawa S, Bessho A, Hisamoto-Sato A, Kubo T, Oze I, Takigawa N, Tanimoto M, Kiura K. Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. J Thorac Oncol. 2015 Mar;10(3):486-91. doi: 10.1097/JTO.0000000000000434.

  PMID: 25695221 RESULT

• Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S, Massuti B, Palmero R, Aix SP, Carcereny E, Fruh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, Froesch P, Reguart N, Puente J, Coate L, Barlesi F, Rauch D, Thomas M, Camps C, Gomez-Codina J, Majem M, Porta R, Shah R, Hanrahan E, Kammler R, Ruepp B, Rabaglio M, Kassapian M, Karachaliou N, Tam R, Shames DS, Molina-Vila MA, Stahel RA; BELIEF collaborative group. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2017 May;5(5):435-444. doi: 10.1016/S2213-2600(17)30129-7. Epub 2017 Apr 10.

  PMID: 28408243 RESULT

• Ninomiya T, Nogami N, Kozuki T, Harada D, Kubo T, Ohashi K, Kuyama S, Kudo K, Bessho A, Fukamatsu N, Fujimoto N, Aoe K, Shibayama T, Sugimoto K, Takigawa N, Hotta K, Kiura K. A phase I trial of afatinib and bevacizumab in chemo-naive patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404. Lung Cancer. 2018 Jan;115:103-108. doi: 10.1016/j.lungcan.2017.11.025. Epub 2017 Nov 28.

  PMID: 29290249 RESULT

• Porta R, Sanchez-Torres JM, Paz-Ares L, Massuti B, Reguart N, Mayo C, Lianes P, Queralt C, Guillem V, Salinas P, Catot S, Isla D, Pradas A, Gurpide A, de Castro J, Polo E, Puig T, Taron M, Colomer R, Rosell R. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J. 2011 Mar;37(3):624-31. doi: 10.1183/09031936.00195609. Epub 2010 Jul 1.

  PMID: 20595147 RESULT

• Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.

  PMID: 29151359 RESULT

• Han B, Li K, Zhao Y, Li B, Cheng Y, Zhou J, Lu Y, Shi Y, Wang Z, Jiang L, Luo Y, Zhang Y, Huang C, Li Q, Wu G. Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). Br J Cancer. 2018 Mar 6;118(5):654-661. doi: 10.1038/bjc.2017.478. Epub 2018 Feb 13.

  PMID: 29438373 RESULT

• Becker A, Crombag L, Heideman DA, Thunnissen FB, van Wijk AW, Postmus PE, Smit EF. Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. Eur J Cancer. 2011 Nov;47(17):2603-6. doi: 10.1016/j.ejca.2011.06.046. Epub 2011 Jul 23.

  PMID: 21784628 RESULT

MeSH Terms

Conditions

Neoplasm Metastasis; Adenocarcinoma of Lung

Interventions

osimertinib; anlotinib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 9, 2021
• First Posted: February 25, 2021
• Study Start: November 19, 2020
• Primary Completion: June 20, 2024
• Study Completion: June 20, 2024
• Last Updated: August 15, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)