Nab-sirolimus in Recurrent High Grade Glioma and Newly Diagnosed Glioblastoma

A Phase 2, Open-label Study of ABI-009 (Nab-Rapamycin) in Patients With Recurrent High-grade Glioma and Patients With Newly Diagnosed Glioblastoma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03463265

Enrollment

Registered

2018-03-13

Start date

2018-08-01

Completion date

2022-08-26

Last updated

2023-11-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

High Grade Recurrent Glioma and Newly Diagnosed Glioblastoma

Brief summary

Phase 2, open-label study of nab-sirolimus in patients with recurrent high grade glioma following prior therapy and patients with newly diagnosed glioblastoma. nab-Sirolimus was administered as single agent or in combination therapies.

Detailed description

A phase 2, open-label study of nab-sirolimus (also known as ABI-009, nab-rapamycin, albumin-bound rapamycin) in patients with recurrent high grade glioma following prior therapy and patients with newly diagnosed glioblastoma. nab-Sirolimus was administered as single agent or in combination therapies, including temozolomide, bevacizumab, lomustine, and marizomib.

Interventions

DRUGnab-sirolimus

nab-sirolimus, single agent

DRUGnab-sirolimus + temozolomide

temozolomide, combination

DRUGnab-sirolimus + bevacizumab

bevacizumab, combination

DRUGnab-sirolimus + lomustine

lomustine, combination

DRUGnab-sirolimus + marizomib (MRZ)

marizomib (MRZ), combination

DRUGnab-sirolimus + temozolomide + radiotherapy

temozolomide + radiotherapy, combination

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Specific for Arm A 1. All subjects must have histologic evidence of high grade glioma (World Health Organization \[WHO\] grade 3 or grade 4) and radiographic evidence of recurrence or disease progression (defined as either a greater than 25% increase in the largest bi-dimensional product of enhancement, a new enhancing lesion, or a significant increase in T2 FLAIR). Subjects must have at least 1 measurable lesion by RANO criteria (≥ 10 mm in 2 perpendicular diameters). 2. Patients must have previously failed a treatment regimen, including radiation and/or chemotherapy. 3. No prior treatment with mTOR inhibitors. 4. No prior treatment with temozolomide for the treatment of recurrent glioma for patients entering the ABI-009 + temozolomide cohort. 5. No prior treatment with bevacizumab or any other anti-angiogenic agents, including sorafenib, sunitinib, axitinib, pazopanib, or cilengitide for the ABI-009 + bevacizumab arm. 6. No prior treatment with lomustine for the ABI-009 + lomustine arm. 7. No prior treatment with marizomib or any other proteasome inhibitors, including bortezomib, carfilzomib, or ixazomib, for patients entering the ABI-009 + marizomib cohort. 8. At least 4 weeks from surgical resection and at least 12 weeks from the end of radiotherapy prior to enrollment in this study, unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there are two MRIs confirming progressive disease that are approximately 4 weeks apart. Inclusion Criteria Specific for Arm B 1. Histologically confirmed newly diagnosed glioblastoma. 2. Patients must have had surgery and can have either non-measurable disease or a measurable post-contrast lesion after surgery detected by MRI. 3. No prior treatment with mTOR inhibitors, and no prior local or systemic therapy for GBM.

Exclusion criteria

Common for Both Arms A and B A patient will not be eligible for inclusion in this study if any of the following criteria apply: 1. Co-medication or concomitant therapy that may interfere with study results, including anti-coagulants and enzyme-inducing anti-epileptic drugs (EIAEDs). 2. History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months. 3. Pregnant or breast feeding. 4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics & psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state. 5. Active gastrointestinal bleeding. 6. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥90 mm Hg. 7. Patients with history of intestinal perforations, fistula, hemorrhages and/or hemoptysis ≤6 months prior to first study treatment. 8. Uncontrolled diabetes mellitus as defined by HbA1c \>8% despite adequate therapy. 9. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. 10. Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving the first dose of ABI-009. Additionally, use of any known CYP3A4 substrates with narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfanide) within the 14 days prior to receiving the first dose of ABI-009. 11. Known other previous/current malignancy requiring treatment within ≤ 3 years except for limited disease treated with curative intent, such as in situ prostate cancer, intracapsular renal cancer, cervical carcinoma in situ, squamous or basal cell skin carcinoma, and superficial bladder carcinoma. 12. Any comorbid condition that restricts the use of study drug and confounds the ability to interpret data from the study as judged by the Investigator or Medical Monitor. 13. Known Human Immunodeficiency Virus (HIV), or active Hepatitis B or Hepatitis C.

Design outcomes

Primary

Measure	Time frame	Description
ORR	Through study completion (up to 48 months)	Objective overall response rate (ORR, according to Response Assessment in Neuro-Oncology \[RANO\]) by investigator-assessed radiologic review and defined as the proportion of patients who achieved a confirmed partial response (PR) or confirmed complete response (CR) per RANO 2010 criteria. PR is defined as greater than or equal to 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks.

Secondary

Measure	Time frame	Description
Median PFS	Through study completion (up to 48 months)	Progression-free Survival defined as number of months from the date of the first dose of study drug to the first observation of a disease progression or death due to any cause. Progression is assessed according to Response Assessment in Neuro-Oncology (RANO) 2010 criteria based on MRI imaging, and includes ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids.
PFS Rate at 6 Months and 12 Months	6 and 12 months	Progression-free survival rate at 6 months and 12 months was calculated as the proportion of patients who were progression-free and alive at 6 and 12 months, respectively. Progression is assessed according to Response Assessment in Neuro-Oncology (RANO) 2010 criteria based on MRI imaging, and includes ≥25% increase in the sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids.
OS	Through study completion (up to 48 months)	Median Overall Survival
OS at 12 Months	12 months	Overall Survival rate at 12 months

Countries

United States

Participant flow

Participants by arm

Arm	Count
Arm A: Nab-sirolimus in Patients With Recurrent High Grade Glioma nab-sirolimus (ABI-009, nab-rapamycin, albumin-bound rapamycin): 100 mg/m2 as a 30-minute IV infusion on Days 1 and 8 of every 21-day cycle. Two dose reduction levels allowed for toxicities: 75 mg/m2 and 60 mg/m2	7
Arm A: Nab-sirolimus + Bevacizumab in Patients With Recurrent High Grade Glioma ABI-009: IV 60 mg/m 2 as a 30-minute infusion on Days 1, 8, and 15 of every 28-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 mg/m2. Three dose reduction levels allowed: 45, 30, and 20 mg/m2. Bevacizumab: IV infusion (90 minutes 1st dose, 60 minutes 2nd dose, and 30 minutes afterward assuming tolerability) at a fixed dose of 5 mg/kg on Days 1 and 15 of every 28-day cycle. Bevacizumab administered approximately 10 minutes after the end of the ABI-009.	6
Arm A: Nab-sirolimus + Temozolomide in Patients With Recurrent High Grade Glioma ABI-009: 60 mg/m 2 as a 30-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 mg/m2. Three dose reduction levels allowed: 45, 30, and 20 mg/m2. Temozolomide: PO at 50 mg/m2 daily.	9
Arm A: Nab-sirolimus + Lomustine in Patients With Recurrent High Grade Glioma ABI-009: 60 mg/m 2 as a 30-minute IV infusion on Days 1 and 8 of every 21-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 mg/m2. Three dose reduction levels allowed: 45, 30, and 20 mg/m2. Lomustine (CCNU): PO at 90 mg/m2 on Day 1 of each odd 21-day cycle (ie, every 6 weeks)	4
ArmA: Nab-sirolimus + Marizomib (MRZ) in Patients With Recurrent High Grade Glioma ABI-009: 60 mg/m 2 as a 30-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 mg/m2. Three dose reduction levels allowed for toxicities: 45, 30, and 20 mg/m2. MRZ: 0.8 mg/m 2 as a 10-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle. MRZ administered approximately 10 minutes after the end of the ABI-009 infusion.	10
Arm B: Nab-sirolimus + Temozolomide + Radiotherapy in Patients With Newly Diagnosed Glioblastoma Concomitant Treatment: starting 1 week after the completion of Induction Treatment and lasting for 6 weeks (2 cycles). ABI-009: IV at 60 mg/m2 as a 30-minute IV infusion on Days 8 and 15 of every 21-day cycle. Three dose reduction levels allowed: 45, 30, and 20 mg/m2. Temozolomide: 75 mg/m2 PO daily for 6 weeks. Focal RT: daily at 30 x 200 cGy, 5 days/week for a total dose of 60 Gy (or equivalent regimens as per RTOG guidelines)	26
Total	62

Baseline characteristics

Characteristic	Arm A: Nab-sirolimus + Temozolomide in Patients With Recurrent High Grade Glioma	ArmA: Nab-sirolimus + Marizomib (MRZ) in Patients With Recurrent High Grade Glioma	Arm B: Nab-sirolimus + Temozolomide + Radiotherapy in Patients With Newly Diagnosed Glioblastoma	Total	Arm A: Nab-sirolimus in Patients With Recurrent High Grade Glioma	Arm A: Nab-sirolimus + Bevacizumab in Patients With Recurrent High Grade Glioma	Arm A: Nab-sirolimus + Lomustine in Patients With Recurrent High Grade Glioma
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	1 Participants	13 Participants	20 Participants	2 Participants	2 Participants	0 Participants
Age, Categorical Between 18 and 65 years	7 Participants	9 Participants	13 Participants	42 Participants	5 Participants	4 Participants	4 Participants
Age, Continuous	60 years	52.5 years	64 years	60 years	60 years	53.5 years	53 years
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants	3 Participants	3 Participants	13 Participants	0 Participants	4 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants	7 Participants	23 Participants	48 Participants	6 Participants	2 Participants	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	0 Participants	3 Participants	2 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	9 Participants	9 Participants	25 Participants	58 Participants	5 Participants	6 Participants	4 Participants
Region of Enrollment United States	9 participants	10 participants	26 participants	62 participants	7 participants	6 participants	4 participants
Sex: Female, Male Female	1 Participants	3 Participants	6 Participants	15 Participants	2 Participants	2 Participants	1 Participants
Sex: Female, Male Male	8 Participants	7 Participants	20 Participants	47 Participants	5 Participants	4 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	7 / 7	4 / 6	8 / 9	4 / 4	10 / 10	19 / 26
other Total, other adverse events	7 / 7	6 / 6	8 / 9	4 / 4	10 / 10	26 / 26
serious Total, serious adverse events	0 / 7	0 / 6	0 / 9	1 / 4	0 / 10	1 / 26

Outcome results

Primary

ORR

Objective overall response rate (ORR, according to Response Assessment in Neuro-Oncology \[RANO\]) by investigator-assessed radiologic review and defined as the proportion of patients who achieved a confirmed partial response (PR) or confirmed complete response (CR) per RANO 2010 criteria. PR is defined as greater than or equal to 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks.

Time frame: Through study completion (up to 48 months)