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

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.

Study Overview

• Status: Completed
• Conditions: High Grade Recurrent Glioma and Newly Diagnosed Glioblastoma
• Intervention / Treatment: 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

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.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Fullerton, California, United States, 92835
      • St. Joseph Heritage Healthcare
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital Presbyterian
    • Santa Monica, California, United States, 90404
      • John Wayne Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A, Cohort 1: nab-sirolimus in patients with recurrent high grade glioma; 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; nab-sirolimus, single agent
Experimental: Arm A, Cohort 2: nab-sirolimus + temozolomide (TMZ) in patients with recurrent high grade glioma; 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; temozolomide, combination; Other Names: temozolomide; nab-sirolimus
Experimental: Arm A, Cohort 3: nab-sirolimus + bevacizumab in patients with recurrent high grade glioma; 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; bevacizumab, combination; Other Names: bevacizumab; nab-sirolimus
Experimental: Arm A, Cohort 4: nab-sirolimus + lomustine (CCNU) in patients with recurrent high grade glioma; 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; lomustine, combination; Other Names: nab-sirolimus; lomustine (CCNU)
Experimental: Arm A, Cohort 5: nab-sirolimus + marizomib (MRZ) in patients with recurrent high grade glioma; 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); marizomib (MRZ), combination; Other Names: nab-sirolimus; marizomib (MRZ)
Experimental: Arm B: nab-sirolimus + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma; 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; temozolomide + radiotherapy, combination; Other Names: radiation; temozolomide; nab-sirolimus

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Aadi Bioscience, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Actual): August 26, 2022
• Study Completion (Actual): August 26, 2022

Study Registration Dates

• First Submitted: March 5, 2018
• First Submitted That Met QC Criteria: March 10, 2018
• First Posted (Actual): March 13, 2018

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 4, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Glioma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Antifungal Agents; Temozolomide; Bevacizumab; Sirolimus; Lomustine; Temsirolimus; MTOR Inhibitors
• Other Study ID Numbers: GBM-007

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No