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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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High Grade Recurrent Glioma and Newly Diagnosed Glioblastoma

Intervention / Treatment
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* Drug: nab-sirolimus
* Drug: nab-sirolimus + temozolomide
* Drug: nab-sirolimus + bevacizumab
* Drug: nab-sirolimus + lomustine
* Drug: nab-sirolimus + marizomib (MRZ)
* Drug: nab-sirolimus + temozolomide + radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Specific for Arm A 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). Patients must have previously failed a treatment regimen, including radiation and/or chemotherapy. No prior treatment with mTOR inhibitors. No prior treatment with temozolomide for the treatment of recurrent glioma for patients entering the ABI-009 + temozolomide cohort. No prior treatment with bevacizumab or any other anti-angiogenic agents, including sorafenib, sunitinib, axitinib, pazopanib, or cilengitide for the ABI-009 + bevacizumab arm. No prior treatment with lomustine for the ABI-009 + lomustine arm. No prior treatment with marizomib or any other proteasome inhibitors, including bortezomib, carfilzomib, or ixazomib, for patients entering the ABI-009 + marizomib cohort. 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 Histologically confirmed newly diagnosed glioblastoma. Patients must have had surgery and can have either non-measurable disease or a measurable post-contrast lesion after surgery detected by MRI. 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: Co-medication or concomitant therapy that may interfere with study results, including anti-coagulants and enzyme-inducing anti-epileptic drugs (EIAEDs). History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months. Pregnant or breast feeding. 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. Active gastrointestinal bleeding. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥90 mm Hg. Patients with history of intestinal perforations, fistula, hemorrhages and/or hemoptysis ≤6 months prior to first study treatment. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. 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. 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. 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. Known Human Immunodeficiency Virus (HIV), or active Hepatitis B or Hepatitis C.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A, Cohort 1: nab-sirolimus in patients with recurrent high grade glioma<br>nab-Sirolimus (ABI-009, nab-rapamycin, albumin-bound rapamycin) was administered at 100 mg/m2 as a 30-minute IV infusion on Days 1 and 8 of every 21-day cycle. | Drug: nab-sirolimus<br>* nab-sirolimus, single agent<br>|
| Experimental: Arm A, Cohort 2: nab-sirolimus + temozolomide (TMZ) in patients with recurrent high grade glioma<br>nab-Sirolimus (60 mg/m 2 as a 30-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle). Temozolomide (PO at 50 mg/m2 daily) | Drug: nab-sirolimus + temozolomide<br>* temozolomide, combination<br>* Other names: temozolomide;|
| Experimental: Arm A, Cohort 3: nab-sirolimus + bevacizumab in patients with recurrent high grade glioma<br>nab-Sirolimus (IV 60 mg/m 2 as a 30-minute infusion on Days 1, 8, and 15 of every 28-day cycle). Bevacizumab (IV at a fixed dose of 5 mg/kg on Days 1 and 15 of every 28-day cycle). | Drug: nab-sirolimus + bevacizumab<br>* bevacizumab, combination<br>* Other names: bevacizumab;|
| Experimental: Arm A, Cohort 4: nab-sirolimus + lomustine (CCNU) in patients with recurrent high grade glioma<br>nab-Sirolimus was administered at 60 mg/m 2 as a 30-minute IV infusion on Days 1 and 8 of every 21-day cycle. CCNU was administered PO at 90 mg/m2 on Day 1 of each odd 21-day cycle (ie, every 6 weeks). | Drug: nab-sirolimus + lomustine<br>* lomustine, combination<br>* Other names: lomustine (CCNU);|
| Experimental: Arm A, Cohort 5: nab-sirolimus + marizomib (MRZ) in patients with recurrent high grade glioma<br>nab-Sirolimus was administered at 60 mg/m 2 as a 30-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle. MRZ was administered at 0.8 mg/m 2 as a 10-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle. MRZ was administered approximately 10 minutes after the end of the nab-sirolimus infusion. | Drug: nab-sirolimus + marizomib (MRZ)<br>* marizomib (MRZ), combination<br>* Other names: marizomib (MRZ);|
| Experimental: Arm B: nab-sirolimus + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma<br>Induction Treatment (4 weeks) with nab-sirolimus (60 mg/m2 IV weekly); followed by Concomitant Treatment (standard of care; 2 cycles): nab-sirolimus (60 mg/m2 IV on Days 8 and 15 of every 21-day cycle) in combination with TMZ (75 mg/m2 PO daily for 6 weeks) + radiotherapy (30 × 200 cGy, 5 days/week); followed by Adjuvant Treatment (6 cycles) starting 4 weeks after Concomitant Treatment, with nab-sirolimus(60 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle) in combination with TMZ (150 mg/m2 PO daily on Days 1-5 of every 28-day cycle) | Drug: nab-sirolimus + temozolomide + radiotherapy<br>* temozolomide + radiotherapy, combination<br>* Other names: radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Through study completion (up to 48 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median PFS | 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. | Through study completion (up to 48 months) | 
| PFS Rate at 6 Months 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. | 6 and 12 months | 
| OS | Median Overall Survival | Through study completion (up to 48 months) | 
| OS at 12 Months | Overall Survival rate at 12 months | 12 months |