Neoplasms

Symptoms and General Pathology

All Conditions

Neoplasm Metastasis

All Drugs and Chemicals

Mitogens

Patients will be treated with NX-019 in multiple ascending cohorts.

Patients will be treated with the REDs of NX-019 as determined in Part 1.

NX-019

Nalo Therapeutics

This is a 2-part, first-in-human, open-label study to determine the safety and tolerability of NX-019 and preliminary efficacy in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutant cancer.

Part 1: The primary objective of Part 1 of this study is to evaluate the safety and tolerability of NX-019 and to determine the maximum tolerated dose (MTD)/Recommended Expansion Dose(s) (REDs).

Part 2: The primary objective of Part 2 of this study is to confirm the safety and tolerability of NX-019 at the REDs and, for each expansion cohort, the preliminary evidence of efficacy as measured by objective response rate (ORR).

A Study of NX-019 in Patients With Advanced, Epidermal Growth Factor Receptor (EGFR) Mutant Cancer

A First-in-Human, Open-Label, Dose Escalation and Expansion Study of Orally Administered NX-019 in Patients With Advanced, EGFR Mutant Cancer

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

Nalo Therapeutics Inc.

Skin and Connective Tissue Diseases

Nervous System Diseases

Breast Neoplasms

Neoplasms, Second Primary

Brain Neoplasms

Meningeal Carcinomatosis

Breast Diseases

Skin Diseases

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Meningeal Neoplasms

Antineoplastic Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Etoposide

Bevacizumab

Methotrexate

Cisplatin

Etoposide phosphate

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Folinic Acid

Folate

Vitamin B9

Bevacizumab (15mg/kg) on D1, etoposide (70mg/m2) on D2-D4, cisplatin (70mg/m2) on D2; 21 days a cycle, for a maximum of 6 cycles

Bevacizumab, etoposide, cisplatin

Additional intrathecal methotrexate only given in patients with leptomeningeal metastasis

Intrathecal methotrexate

Yen-Shen Lu, MD, PhD

The main purpose of this study is to investigate the efficacy of bevacizumab, etoposide and cisplatin in treating breast cancer patients with central nervous system metastasis (including brain parenchymal and leptomeningeal metastasis).

Brain metastases are increasingly important causes of morbidity and mortality in breast cancer patients. Whole brain radiotherapy (WBRT) and surgery remains the standard treatment for brain metastases. However, the median overall survival after brain and leptomeningeal metastasis were only 8.5 months and 16 weeks respectively There is lack of standard treatment for brain metastasis progression post WBRT. Chemotherapy was considered mostly poor for treatment response because of the blood brain barrier. However, this has been questioned because tumor can disrupt the normal function of blood brain barrier. For example, etoposide and cisplatin had been used for treatment for breast cancer patients with brain metastasis. The overall response rate of central nervous system (CNS) was 39 %, disease control rate was 60%, although the median overall survival was 31 weeks only. The role of targeted therapies is actively being assessed. Recently, a phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer showed that CNS objective response rates were 6% to lapatinib monotherapy and 20% to lapatinib plus capecitabine. Although the result is promising, the treatment population is limited in the HER2 overexpression breast cancer.

Bevacizumab, an anti-angiogenic agent, has been approved to combine with several chemotherapy agents in breast, lung and colon cancer. It was once considered contraindicated in patients with brain metastases due to the possibility of intracranial bleeding. However, two studies involving the use of bevacizumab for treating brain metastatic tumors of non-squamous or peripherally located squamous lung cancer showed no report of brain hemorrhage. In addition, bevacizumab has been approved to treat primary brain aggressive tumors recently.

In the institution, the investigators treated three breast cancer patients with multiple brain metastases using bevacizumab plus etoposide and cisplatin (B-EP). All of them have been treated for at least two lines of chemotherapy before brain metastases occurred. All of them received WBRT for brain metastases and one of them also received craniotomy with brain tumor resection plus local stereotactic radiosurgery. The follow up magnetic resonance imaging (MRI) had revealed recurrent metastatic brain tumors in one patients, and recurrence of leptomeningeal metastasis in another two patients. One patient who has multiple brain parenchyma metastases showed objective response on MRI after two cycle of B-EP treatment, and remained progression free for more than 5 months. The other two patients with leptomeningeal metastasis had intrathecal and intraventricular (via Ommaya reservoir) methotrexate treatment for more than eight doses. They were near stupor before B-EP treatment. Both had best clinical response of full recovery of consciousness and absence of cancer cells in cerebrospinal fluid. One survived eight months after the diagnosis leptomeningeal metastasis, and the other two were still alive six months after the diagnosis of leptomeningeal metastasis .

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been used in various studies for evaluation of anti-angiogenic condition. In breast cancer, DCE-MRI has been used as an early predictive marker for response. Glioblastoma patients have also been evaluated with DCE-MRI to determine reduction of vessel permeability after bevacizumab treatment.

Proton magnetic resonance spectroscopy (1H-MRS) has been used to different benign brain tumors from malignant ones. The utilization of 1H-MRS, especially in human brain tumors, coupled to both routine MRI and functional MRI techniques provides greater information concerning tumor grading and extension and characterization of the normal surrounding tissue than what is possible with any other imaging technique alone. To analyze proton spectroscopy before and after bevacizumab may give us further information about the mechanism of B-EP on CNS metastasis.

Therefore, the investigators propose to conduct a phase II clinical trial to test the efficacy of B-EP regimen in breast cancer patients with CNS metastasis along with brain DCE-MRI to demonstrate the antiangiogenesis efficacy.

Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis

A Phase II Study of Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis

The response criteria for brain parenchymal metastasis is measured according to the volumetric response criteria with modification. CNS lesion(s) which have a ≧ 50% volumetric reduction of in the absence of progressive neurologic signs and symptoms will be considered as responsive.

The response criteria for leptomeningeal metastasis is defined as disappearance of carcinoma cells of three consecutive cytology examination of cerebrospinal fluid (CSF) after chemotherapy. For patients with both brain and leptomeningeal metastases, both criteria need to be met to be considered as responsive.

To observe the toxicity profile of B-EP according to CTCAE 3.0

To use volumetric measurement by subtraction image of CT the tumor before and after contrast enhancement; assessed every 9 weeks until best response measured

A response is defined as the CSF cytology examination turns from positive to negative. A confirmed response is defined as CSF cytology examination remains negative for two or three consecutive tests

To evaluate the response rate of extra-CNS lesions according to RECIST. Measure every 9 weeks until best response recorded

vascular activity detected with dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), measured before treatment, 24 hours after bevacizumab administration and end of 1st cycle of B-EP

Prognostic and predictive value of biomarkers in CSF or serum. Serum will be drawn before treatment, end of cycle one and end of 6 cycles of treatment or time of progression

Drug concentrations of bevacizumab, etoposide in CSF, blood and CSF/blood ratio before and after B-EP treatment in cycle one and cycle two

To evaluate the response rate and duration of response of CNS metastasis regarding to prior exposure to cisplatin

To evaluate the characteristics of 1H-MRS of metastatic brain tumor before and after B-EP treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of NX-019 in Patients With Advanced, Epidermal Growth Factor Receptor (EGFR) Mutant Cancer	NCT05514496	EGFR Mutation-R...	NX-019	18 Years -	Nalo Therapeutics Inc.
A Study of NX-019 in Patients With Advanced, Epidermal Growth Factor Receptor (EGFR) Mutant Cancer	NCT05514496	EGFR Mutation-R...	NX-019	18 Years -	Nalo Therapeutics Inc.
Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis	NCT01281696	Breast Neoplasm... Leptomeningeal ... Brain Metastase...	Bevacizumab, et... Intrathecal met...	18 Years - 75 Years	National Taiwan University Hospital
Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis	NCT01281696	Breast Neoplasm... Leptomeningeal ... Brain Metastase...	Bevacizumab, et... Intrathecal met...	18 Years - 75 Years	National Taiwan University Hospital

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