Phase 2 Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase 2 trial evaluates how well pegylated irinotecan (NKTR-102) works in treating patients with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or breast cancer (mBC) that has spread to the brain and does not respond to treatment. Pegylated irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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Primary Objective: For cohort A and Cohort C, to determine the central nervous system (CNS) disease control rate (number of patients with stable disease or partial response or complete response / total number of treated patients) at 12 weeks following treatment with etirinotecan pegol in patients with advanced non-small cell lung cancer (NSCLC) or with metastatic brain cancer (mBC) with refractory brain metastases Secondary Objectives: Cohorts A and C: To measure the overall disease control rate and response rate for patients receiving study therapy To measure the systemic (non-CNS) disease control rate and response rate for patients receiving study therapy To observe the progression free survival of the study population To observe the overall survival of the study population Cohort B: • To observe CNS and systemic disease control in small cell lung cancer (SCLC) Cohorts A, B and C: • To determine the safety profile of etirinotecan pegol

Official Title
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A Phase 2 Study of Etirinotecan Pegol (NKTR-102) in Patients With Refractory Brain Metastases and Advanced Lung Cancer or Metastatic Breast Cancer (MBC)

Conditions
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Stage IV Non-small Cell Lung Cancer (NSCLC), Recurrent Non-small Cell Lung Cancer (NSCLC), Extensive-stage Small Cell Lung Cancer (SCLC), Recurrent Small Cell Lung Cancer (SCLC), Tumors Metastatic to Brain, Metastatic Breast Cancer (mBC)

Intervention / Treatment
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* Drug: Pegylated Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age. Life expectancy of 3 months or longer. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Advanced or refractory cancer, consisting of Metastatic breast cancer (mBC) for which single-agent cytotoxic chemotherapy is indicated. OR Histologically-proven metastatic lung cancer: Non-small cell lung cancer (NSCLC) as Stage IV disease or recurrent metastatic disease [per lung cancer tumor, node and metastasis (TNM) classification system, 7th ed] (Cohort A) OR Small cell lung cancer (SCLC) as extensive stage or recurrent metastatic disease (cohort B), including tumors with mixed small cell and non-small cell elements. Prior chemotherapy (at least one of the following): At least one line of prior systemic chemotherapy At least one line of prior targeted treatment for metastatic disease Adjuvant systemic chemotherapy within prior 6 months Prior treatment for metastatic breast cancer (mBC) must have included taxane-based regimen Prior chemotherapy, including other investigational therapy, has been completed prior to initiation of study treatment, according to the following: ≥ 2 weeks if immediately preceding treatment was chemotherapy/targeted therapy administered on a daily or weekly schedule ≥ 3 weeks if immediately preceding treatment was chemotherapy/targeted therapy administered every 2 weeks ≥ 4 weeks if immediately preceding treatment was chemotherapy/targeted therapy administered every 3 weeks Previously received at least one CNS directed treatment (such as surgery or radiation) OR not be eligible for CNS stereotactic radiosurgery Measurable CNS disease, either previously untreated (not counting systemic therapy), or progressed following previous radiation treatment. Lesions that have progressed after prior radiosurgery should not be selected as measurable disease if they are suspected of being radionecrosis. The following measurement criteria are required, as visualized by contrast-enhanced MRI with slice thickness of ≤ 1.5 mm, unless absence of contrast or thicker slices is specifically authorized by Protocol Director. Measurements do not include tumor edema. At least one CNS tumor measuring ≥ 10 mm in longest diameter, OR At least one CNS tumor measuring 5-9 mm in longest diameter, plus one or two additional CNS tumors measuring ≥ 3 mm in longest diameter, for which the sum of the longest diameters is ≥ 10 mm. Additional tumors are not exclusionary. Adequate organ function as evidenced by: Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L without G-CSF (filgrastim, pegfilgrastim, or equivalent) support within 7 days Hemoglobin (Hgb) ≥ 9.0 g/dL (90 g/L) without blood transfusion within 7 days Platelet count ≥ 100 x 10e9/L without platelet transfusion within 7 days Bilirubin ≤ 1.5 X upper limit of normal (ULN), except for patients with documented history of Gilbert's disease who may have DIRECT bilirubin ≤ 1.5 X ULN Alanine aminotransferase (ALT) ≤ 2.5 X ULN, except ≤ 5 X ULN for patients with liver metastases Aspartate aminotransferase (AST) ≤ 2.5 X ULN, except ≤ 5 X ULN for patients with liver metastases Serum creatinine ≤ 1.5 X ULN; or calculated creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault formula), or measured creatinine clearance ≥ 50 mL/min. Exclusion Criteria: Previous treatment with a camptothecin derivative (eg, irinotecan, topotecan, and investigational agents including but not limited to exatecan, rubitecan, gimatecan, karenitecin, SN38 investigational agents, EZN 2208, SN 2310, and AR 67) is not allowed Patients may not have a known history of leptomeningeal disease, as diagnosed by positive CSF cytology, unless prospective permission for enrollment is granted from the sponsor and the PI Patients may not have had major surgery or radiotherapy (therapeutic and/or palliative) within 14 days prior to initiation of study treatment, including CNS-directed radiation therapy. Minor procedures, such as tumor biopsy, thoracentesis, or intravenous catheter placement are allowed with no waiting period Patients may not have the following co morbid disease or concurrent illness: Chronic or acute gastrointestinal (GI) disorders resulting in diarrhea of any severity grade; patients may not use chronic anti-diarrheal supportive care (more than 3 days/week) to control diarrhea in the 28 days prior to first dose of investigational drug. (exception: anti-diarrheal medications used to control symptoms from a medication that will be discontinued prior to study are allowed with a 7 day washout before study therapy, for example loperamide for erlotinib-associated diarrhea) Known cirrhosis, defined as Child Pugh class A or higher liver disease Other active malignancy, except for non melanoma skin cancer and carcinoma in situ (of the cervix or bladder) Any other severe/uncontrolled inter current illness or significant co morbid conditions that in the opinion of the investigator would impair study participation or cooperation Patients may not have a known allergy or hypersensitivity to any of the components of the investigational therapy, including polyethylene glycol (PEG) or topoisomerase inhibitors Patients may not be receiving the following medications at the time of first dose of investigational drug: Pharmacotherapy for known hepatitis B or C, tuberculosis, or human immunodeficiency virus (HIV) Any of the following enzyme inducing anti epileptic medications (EIAEDs): phenytoin, carbamazepine, oxcarbazepine, phenobarbital Other chemotherapy, hormonal therapy, immunotherapy, other investigational agents, or biologic agents for the treatment of cancer except for bisphosphonates or denosumab Pregnant or nursing patients will be excluded from the study

Ages Eligible for Study
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Minimum Age: 18 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: Cohort A - Pegylated Irinotecan to treat NSCLC<br>Patients with non-small cell lung carinoma (NSCLC) will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Pegylated Irinotecan<br>* Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)<br>* Other names: etirinotecan pegol;|
| Experimental: Cohort B - Pegylated Irinotecan to treat SCLC<br>Patients with small cell lung carinoma (SCLC) will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Pegylated Irinotecan<br>* Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)<br>* Other names: etirinotecan pegol;|
| Experimental: Cohort C - Pegylated Irinotecan to treat mBC<br>Patients with metastatic breast cancer (MBC) to brain will receive pegylated irinotecan intravenously (IV) over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Pegylated Irinotecan<br>* Administered intravenously (IV) at 145 mg/m² as monotherapy once every 21 days (1 cycle)<br>* Other names: etirinotecan pegol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central Nervous System (CNS) Disease Control Rate (Cohort A and C) | Central nervous system (CNS) disease control (DC) is defined as a complete response (CR); partial response (PR); or stable disease (SD). The outcome is reported as the number and percentage of participants who achieve DC, a number without dispersion. Response criteria are as follows. Note that any lesion less than 10 mm in longest diameter (LD) is considered unchanged unless there is a ≥ 3 mm change in the sum of the LDs. CR = Disappearance of all target lesions, sustained for ≥ 4 weeks with no new lesions; clinical condition stable or improved PR = ≥ 30% decrease in target lesion LD and no new lesions, sustained for ≥ 4 weeks; clinical condition stable or improved PD (progressive disease) = Any of 20% increase in target lesion LD; increase in T2/FLAIR non-enhancing lesions; any new lesions; non-target progression; or clinical deterioration SD = Neither PR or PD | At 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Disease Control Rate (Cohort A and C) | Overall disease control (DC) rate is defined as the sum in a cohort of the numbers of participants achieving complete response (CR); partial response (PR); or stable disease (SD), divided by the number of patients in that cohort. For this outcome, overall means all body systems, not just the central nervous system (CNS). The outcome is reported as DC rate, a number without dispersion. Response criteria are as follows. Note that any lesion <10 mm in longest diameter (LD) is considered unchanged unless there is a ≥3 mm change in the sum of the LDs. CR = Disappearance of all target lesions, sustained for ≥4 weeks with no new lesions; clinical condition stable or improved PR = ≥30% decrease in target lesion LD & no new lesions, sustained for ≥ 4 weeks; clinical condition stable or improved PD = Any of: 20% increase in target lesion LD; increase in T2/FLAIR non-enhancing lesions; any new lesions; non-target progression; or clinical deterioration SD = Neither PR or PD | At 12 weeks | 
| Overall Response Rate (Cohort A and C) | Overall response by subject (OR) is defined as the lower assessment between the central nervous system response and the systemic response. Response is defined as either complete response (CR) or partial response (PR). The outcome is reported as the number and percentage of participants who achieve OR, a number without dispersion. Response criteria are as follows. Note that any lesion < 10 mm in longest diameter (LD) is considered unchanged unless there is a ≥ 3 mm change in the sum of the LDs. CR = Disappearance of all lesions, sustained for ≥ 4 weeks with no new lesions; clinical condition stable or improved PR = ≥ 30% decrease in target lesion LD & no new lesions, sustained for ≥ 4 weeks; clinical condition stable or improved PD = Any of: 20% increase in target lesion LD; increase in T2/FLAIR non-enhancing lesions; any new lesions; non-target progression; or clinical deterioration SD = Neither PR or PD | At 12 weeks | 
| Systemic (Non-CNS) Disease Control Rate (Cohort A and C) | Systemic (ie, non-central nervous system) disease control (DC) rate by cohort is defined as the number of patients with complete response (CR) + partial response (PR) + stable disease (SD), divided by the total number of patients. The outcome will be reported as DC rate, a number without dispersion. Response criteria are as follows. Note that any lesion < 10 mm in longest diameter (LD) is considered unchanged unless there is a ≥ 3 mm change in the sum of the LDs. CR = Disappearance of all lesions, no new lesions; pathological lymph nodes reduced in short axis to < 10 mm PR = ≥ 30% decrease in sum of lesion diameters; no new lesions; no progression of non-target lesions PD = Any of 20% increase in sum of lesion diameters; progression of non-target lesions; new lesions SD = Neither CR, PR, nor PD | At 12 weeks | 
| Systemic (Non-CNS) Response Rate (Cohort A and C) | Systemic (ie, non-central nervous system) response rate by cohort is defined as the number of participants achieving a complete response (CR) or partial response (PR), divided by the number of participants. The outcome will be reported as a number without dispersion. Response criteria are as follows. Note that any lesion < 10 mm in longest diameter (LD) is considered unchanged unless there is a ≥ 3 mm change in the sum of the LDs. CR = Disappearance of all target lesions, no new lesions; pathological lymph nodes reduced in short axis to < 10 mm PR = ≥ 30% decrease in sum of lesion diameters; no new lesions; no progression of non-target lesions PD = Any of 20% increase in sum of lesion diameters; progression of non-target lesions; new lesions SD = Neither CR, PR, nor PD | At 12 weeks | 
| Progression-free Survival (PFS) (Cohort A and C) | Progression-free survival (PFS) is defined as the time from the date of start of treatment until disease progression or death. The outcome is reported by cohort as PFS in months, with full range. | Date of first dose of pegylated irinotecan NKTR 102 to date of disease progression, assessed up to 2 years | 
| Overall Survival (Cohort A and C) | Overall survival (OS) is defined as the period remaining alive after the start of treatment. The outcome is reported as the median with full range. | 4 years | 
| Central Nervous System (CNS) Disease Control (Cohort B) | Central nervous system (CNS) disease control (DC) is defined as a complete response (CR); partial response (PR); or stable disease (SD). The outcome is reported as the number and percentage of participants who achieve DC, a number without dispersion. Response criteria are as follows. Note that any lesion less than 10 mm in longest diameter (LD) is considered unchanged unless there is a ≥ 3 mm change in the sum of the LDs. CR = Disappearance of all target lesions, sustained for ≥ 4 weeks with no new lesions; clinical condition stable or improved PR = ≥ 30% decrease in target lesion LD and no new lesions, sustained for ≥ 4 weeks; clinical condition stable or improved PD = Any of 20% increase in target lesion LD; increase in T2/FLAIR non-enhancing lesions; any new lesions; non-target progression; or clinical deterioration SD = Neither PR or PD | At 12 weeks | 
| Systemic Disease Control (Cohort B) | Systemic (ie, non-central nervous system) disease control (DC) rate by cohort is defined as the number of patients with complete response (CR) + partial response (PR) + stable disease (SD), divided by the total number of patients. The outcome will be reported as DC rate, a number without dispersion. Response criteria are as follows. Note that any lesion < 10 mm in longest diameter (LD) is considered unchanged unless there is a ≥ 3 mm change in the sum of the LDs. CR = Disappearance of all lesions, no new lesions; pathological lymph nodes reduced in short axis to < 10 mm PR = ≥ 30% decrease in sum of lesion diameters; no new lesions; no progression of non-target lesions PD = Any of 20% increase in sum of lesion diameters; progression of non-target lesions; new lesions SD = Neither CR, PR, nor PD | At 12 weeks | 
| Related Adverse Events (Toxicity) | Toxicity, defined as related adverse events, is reported as the total number of events experienced by the participants in each cohort, a number without dispersion. Related is defined as meaning possibly, probably, or definitely related to the study drug. | Up to 2 years |