PURPOSE:Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570). PATIENTS AND METHODS:Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis. RESULTS:Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation (P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred. CONCLUSION:nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.

Background: mTOR pathway is a key regulator of cell survival and proliferation and has been implicated in various indications, including oncology, hematology, and cardiovascular, metabolic, and central nervous system diseases. ABI-009, a novel mTOR inhibitor, is an intravenously (IV) administered nanoparticle form of albumin-bound sirolimus. ABI-009 is in a registrational clinical study for perivascular epithelioid cell carcinoma (PEComa), and also studied as combination or single agent in phase 1, 1/2, and 2 studies in neuroendocrine tumors, bladder cancer, glioblastoma, soft-tissue sarcomas, colorectal cancer, childhood cancers, as well as pulmonary arterial hypertension and epilepsy. ABI-009 has a distinct PK profile vs. oral mTOR inhibitors, and it is hypothesized that albumin binding to sirolimus may improve drug penetration and thus efficacy. This xenograft study was conducted to evaluate the antitumor activity, tissue penetration, and mTOR inhibition of ABI-009 vs. equal doses of oral mTOR inhibitors at clinically relevant doses. Methods: Athymic mice were injected with UMUC3 bladder cancer cells subcutaneously into both flanks. Upon development of tumors, ABI-009, oral rapamycin and everolimus were administered at equal weekly doses of 15 mg/kg, n = 5 each group: ABI-009 IV at 7.5 mg/kg, 2x /wk; rapamycin and everolimus PO at 3 mg/kg/day, 5 days /wk; saline IV at 10 ml/kg, 3x /wk. Body weights, tumor measurements, and clinical signs were recorded 3x /wk for up to 5 wks of treatment. Tumor and blood drug concentrations were also obtained (tumor: D1 1h and 24h, D4 1h, D7; blood: D4 1h, D7). Markers for mTOR pathway activation (pS6, p4EBP1) will also be analyzed. Results: The tumor growth inhibition (TGI) was 69.6% with ABI-009, significantly greater vs. oral rapamycin (TGI 24.3%; p Conclusions: This study demonstrated significantly greater antitumor activity and prolonged survival at clinically relevant doses with ABI-009 vs. equal weekly dosing of oral mTOR inhibitors, rapamycin and everolimus. The increased efficacy of ABI-009 over the oral mTOR inhibitors may be the result of increased drug exposure and tumor penetration. The lack of significant weight loss indicated acceptable toxicity at the doses studied in each group. These findings warrant further study in the clinical setting. Citation Format: Anita N. Schmid, Shawn Hou, Berta Grigorian, Neil P. Desai. Improved tumor penetration, antitumor activity, and survival of ABI-009 (nab-sirolimus) versus oral rapamycin and everolimus and investigation of mTOR pathway inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B08.

e16050 Background: The PI3K/mTOR pathway overactivation and loss of PTEN occur in 20-40% of mCRC pts. A recent phase 1/2 study in mCRC pts showed evidence that everolimus added to 1L SOC treatment improved outcomes, in particular in pts with PTEN loss (Gilcrease, 2019). This prospective, single-arm phase 1/2 study aims to identify the optimal dose and schedule of nab-sirolimus (ABI-009), an mTOR inhibitor, plus FB and evaluate the safety and preliminary efficacy of this regimen. Methods: Eligible pts have no prior therapy, ≥18 years old, ECOG performance status of 0-2. PTEN loss (by IHC) is evaluated for all pts. nab-Sirolimus IV starting dose and schedule was 30mg/m2 weekly for 3 weeks followed by a week of rest (on D1, 8, and 15 in a 28-day cycle, qw3/4) plus standard doses of FB on D1 and D15. Dose escalation to 45 and 60mg/m2 or de-escalation to 20 and 10mg/m2 followed the 3+3 design. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: As of Jan 31, 2020, 24 pts were treated in the phase 1 study and 18 were evaluable for response. No DLTs were observed in the first 3 pts treated with nab-sirolimus at 30mg/m2 qw3/4; however, all 3 pts missed D8 doses (due to G2 thrombocytopenia and G3 neutropenia) and the cohort expanded to additional 3 pts for further observation. 5/6 pts missed D8 doses and a new dose cohort enrolled pts at 20mg/m2 qw3/4. No DLTs were observed and the cohort was expanded to 10 pts. A safety review of the first 18 pts observed that 9/18 pts missed doses on D8 and a new cohort was added to enroll pts at 20 mg/m2 q2w (D1 and D15, as for FB). This cohort enrolled 8 pts with no DLTs and represents the recommended-phase-2-dose (RP2D) and continues enrollment in phase 2. For all pts, 15/24 (63%) pts had G3-4 treatment-related adverse events (TRAEs); most common were neutropenia (6/24, 25%) and thrombocytopenia (4/24, 17%). At the RP2D 3/8 (38%) pts had G3-4 TRAEs (thrombocytopenia, weight loss, and hypertension, 1 pt each). Among 18 evaluable pts, best response was: 7/18 (39%) partial response, 10/18 (56%) stable disease, and 16/18 (89%) had tumor shrinkage. PTEN was assessed in 14 pts: 4/14 (29%) had PTEN loss, 2/4 (50%) PTEN loss pts responded, while 3/10 (30%) pts that were PTEN+ (WT) had a response. Conclusions: The RP2D of nab-sirolimus is 20mg/m2 q2w in combination with standard mFOLFOX+bevacizumab. The phase 2 portion of the study is ongoing. Clinical trial information: NCT03439462 .

11516 Background: Malignant PEComa is a rare, aggressive sarcoma, with no approved medical treatment. Cytotoxic chemotherapies have limited benefit for patients with advanced disease. The AMPECT trial measured the effects of nab-sirolimus (ABI-009) and is the first prospective study in advanced malignant PEComa. nab-Sirolimus is a nanoparticle albumin-bound mTOR inhibitor with significantly higher intratumoral drug levels, mTOR target suppression, and anti-tumor activity in animal models versus other mTOR inhibitors. This report presents long-term follow-up of DoR after the primary analysis. Methods: Patients (N=34) received nab-sirolimus (100mg/m2 IV, weekly, 2/3 weeks) until progression or unacceptable toxicity. Primary endpoint: ORR by IRR. Key secondary endpoints included DoR, PFS6, OS, and safety. Exploratory endpoints included correlation of tumor genotype and outcome. The sample size of 30 efficacy-evaluable patients was based on an estimated ORR of 30% and the lower bound of the 95%CI of ORR to exclude values less than 14.7%. The primary analysis was conducted when all patients were treated ≥6 months (May 22, 2019). This report updates the primary response analysis and DoR with an additional 8.5-month of follow-up. Results: As of Feb 06, 2020, of the 31 efficacy-evaluable patients, the confirmed ORR by IRR was 39% (12/31, 95%CI: 21.8, 57.8), with 1 complete response (CR) and 11 partial responses (PR), 52% stable disease (SD, 16/31, with 10/16 SD ≥12 weeks), and 10% progressive disease (3/31); the disease control rate (CR+PR+SD ≥12 weeks) was 71%. PFS6 was 71% (95%CI: 47.7, 85.1). The majority of responses (67%) were reached at the first post-baseline scan at week 6, with a median time to response of 1.4 months (95%CI: 1.3 to 2.8). The median DoR by IRR was not yet reached (range 5.6-38.7+ months; calculated median 22.2+ months) with 8/12 (67%) responders still on treatment for >1 year and 5/12 (42%) >2 years. Mutational analysis available for 25 patients identified that TSC2 loss-of-function mutations significantly correlated with response; 8/9 (89%) patients with TSC2 had a confirmed response. Conclusions: Responses of advanced malignant PEComa to nab-sirolimus were highly durable and occurred in 39% of patients based on independent review. The high disease control rate with manageable toxicities suggest that nab-sirolimus is effective and represents an important new treatment option for these patients. NCT02494570. Clinical trial information: NCT02494570 .

TPS730 Background: Very few treatment options are available for pts with mCRC beside the standard of care (SOC), 5-FU based chemotherapy + bevacizumab. Immunotherapy is an option for pts with microsatellite instability (~5% of mCRC). The central role of the PI3K/mTOR pathway in cancer biology, including CRC, suggests that mTOR inhibition along with chemotherapy may improve antitumor activity in the metastatic setting. A recent phase I/II study showed promising antitumor activity of everolimus + SOC as 1L treatment for mCRC (96% progression-free [PF] rate at six months at the maximum tolerated dose (MTD), and 86% ORR for pts with PTEN loss (Gilcrease, ASCO 2012). The goal of this prospective, single arm phase I/II study is to evaluate the efficacy and safety of ABI-009, a novel mTOR inhibitor, + SOC as 1L treatment for mCRC. Methods: Eligible pts have an ECOG performance status of 0-2 and histologically confirmed measurable metastatic disease. PTEN loss (by IHC) and mutational status for PIK3CA, KRAS, NRAS, BRAF by NGS is evaluated for all pts. ABI-009 is given weekly x3 every four weeks starting at 30 mg/m2and can escalate to 45 and 60 mg/m2 (3+3 design); mFOLFOX6 + bevacizumab is given every two weeks. After six cycles of therapy, cycles may change to 21-days: ABI-009 weekly x2 every three weeks and mFOLFOX6 + bevacizumab every three weeks. Pts are treated until disease progression. Tumor response is assessed by CT at baseline then every eight weeks for one year, then every 12 weeks thereafter. Phase I will enroll up to 18 pts; the primary endpoints are dose-limiting toxicities and MTD, secondary endpoints include disease control rate (DCR). Phase II will enroll 40 pts; the primary endpoint is PF rate at six months, and secondary endpoints are median PF survival, overall survival, duration of response, and DCR in the intent-to-treat population and based on PTEN status. This study is now active, with first pt enrolled. The anticipated enrollment period is 12 months. This prospective phase I/II study may show evidence of efficacy and safety of ABI-009 combined with the SOC in pts with mCRC with or without PTEN loss to warrant a larger clinical study. Results: N/A. Conclusions: N/A. Clinical trial information: NCT03439462.

11005 Background: Malignant PEComa is a rare, aggressive sarcoma, with no approved treatment or prior clinical trials. Case reports suggest mTOR activation through mutations or deletions of TSC1 or TSC2 and activity of mTOR inhibitors in this disease. ABI-009 is an albumin-bound mTOR inhibitor with increased tumor uptake. The AMPECT trial is the first prospective study in malignant PEComa. Methods: Eligible patients (pts) with centrally confirmed PEComa receive ABI-009 (100 mg/m2 IV, wkly, 2/3 wks) until progression or unacceptable toxicity. Primary endpoint: ORR by independent review (IR), assessed every 6 wks (RECIST v1.1). Secondary endpoints: duration of response (DOR), PFS6, PFS, and safety. Exploratory endpoints (EE): investigator-assessed (IA) outcomes and mutational status. Sample size: 30 efficacy-evaluable pts based on target ORR of 30% (primary analysis planned when all pts treated ≥6 mo). Results: EE and safety are reported (IR pending). As of Feb 12, 2019, enrollment is complete; 34 pts treated, 31 evaluable for efficacy, 42% (13/31) pts ongoing Rx. IA ORR is 42% PR (13/31, 95% CI: 24.5, 60.9), 35% SD (11/31), and 23% PD (7/31); 69% of PRs were reached at 1st restaging (wk 6); 69% PRs are ongoing, with 5 pts >1yr and 2 pt >2 yrs on Rx (all ongoing). Other IA outcomes: median DOR is not reached; PFS6 is 66%; median PFS is 8.9 mo (95% CI: 5.5, -). The most common (>30%) nonhematologic treatment-related AEs (TRAEs) of any grade: mucositis (65%), fatigue (53%), nausea/weight loss (35% each), diarrhea (32%); the most common (>15%) hematologic TRAEs: anemia (44%) and thrombocytopenia (18%). Pneumonitis (15%) was G1/G2. The most common (>10%) G3 TRAEs: mucositis (18%), anemia (12%); No grade ≥4 TRAEs. TSC1 or TSC2 mutations occurred in 5 and 9 (no overlap) of 25 pts with known mutational status, respectively. PR was seen in 100% (9/9) pts with TSC2 mutation, 20% (1/5) pts with TSC1 mutation, and 9% (1/11) pts without mutation in TSC1 or TSC2, P < 0.0001 (2x3 Fisher exact test). PR was significantly higher in pts with TSC2 mutations vs pts without mutation in TSC1 or TSC2, P = 0.0001 (Fisher exact test). Disease control (PR+SD) was seen in 93% (13/14) pts with TSC1 or TSC2 mutations vs 55% (6/11) pts without mutation in TSC1 or TSC2, P = NS. Conclusions: Preliminary IA outcomes showed that ABI-009 treatment of PEComa resulted in substantial and durable responses with manageable toxicities. TSC2 mutations were associated with IA response. Clinical trial information: NCT02494570.

Abstract BACKGROUND The mTOR pathway is frequently activated in patients with GBM and is associated with reduced survival, making this pathway a promising target. However, mTOR inhibitors, including everolimus and temsirolimus, have poor brain penetration, limiting their potential use for GBM. ABI-009 is a novel albumin-bound mTOR inhibitor that has a distinct PK profile and biodistribution, including CNS penetration. The goal of this prospective, multi-cohort open-label phase 2 study is to evaluate the efficacy and safety of ABI-009 monotherapy and combination therapy in rHGG and ndGBM. METHODS Eligible patients are ≥18 years old, KPS score ≥70, and have histologically confirmed rHGG or ndGBM. Arm A has 5 cohorts in patients with rHGG, naïve to mTOR inhibitors: 1) ABI-009 single agent IV 100 mg/m2; 2–5) ABI-009 60mg/m2 plus TMZ 50mg/m2 or BEV 5mg/kg or marizomib 0.8mg/m2 or CCNU 90mg/m2. In Arm B for patients with ndGBM, ABI-009 100mg/m2 is given weekly for 4 weeks (Induction) after surgery, followed by ABI-009 at 60mg/m2 plus RT/TMZ. Up to 19 patients per cohort will be enrolled: initial 9 patients with a stopping rule that only if there are ≥2 responses will the study proceed to further enrollment of the next 10 patients (Simon’s 2-stage design). Treatment will continue until disease progression or unacceptable toxicity. The primary endpoint for all cohorts is overall response rate per RANO criteria; secondary endpoints are median PFS and OS, 6-month and 12-month PFS, 12-month OS, and safety. This study is open and actively enrolling patients. The anticipated enrollment period is 24 months. NCT03463265

mTOR activation is implicated in the proliferative aspect of PAH. ABI-009, albumin-bound nanoparticle sirolimus, has anti-proliferative activity and high lung accumulation, and is being explored as a novel treatment approach in patients (pts) with severe PAH. This phase 1 study investigates the

TPS11589Background: PEComas are rare mesenchymal tumors with a female predominance, composed of epithelioid cells that show a focal association with blood vessel walls and usually express both mela...

Abstract Background: mTOR pathway has been implicated in cell survival and proliferation and is an attractive target for cancer therapy. Loss of PTEN, a negative regulator of mTOR pathway, is frequently observed in multiple cancer types. Recent studies indicate that loss of PTEN promotes resistance to T cell-mediated immunotherapy. Since PTEN loss can result in downstream mTOR activation, we investigated the safety and efficacy of ABI-009 (nab-rapamycin, a novel mTOR inhibitor) in combination with anti-PD1 antibody in a syngeneic mouse model of B16 melanoma. ABI-009 (nab-rapamycin) is a nanoparticle form of human albumin-bound rapamycin with a mean particle size of approximately 100 nm developed with a proprietary nanoparticle albumin-bound (nab®) technology. ABI-009 is currently in phase 1 and 2 clinical studies for the treatment of malignant perivascular epithelioid cell carcinoma (PEComa), severe pulmonary arterial hypertension (PAH), nonmuscle-invasive bladder cancer, soft-tissue sarcomas, and various childhood cancers. Methods: Syngeneic B16 melanoma tumors were implanted in immunocompetent C57BL/6 mice. ABI-009 was administered IV at 5 mg/kg 3 times weekly. Monoclonal anti-mouse PD-1 antibody (RMP1-14, BioXcell, West Lebanon, NH, USA) was administered IP at 250 μg every 2 days for 3 times. The study drugs were either administered as single agent or in combination with 3 different dosing schedules: concurrent (A), ABI-009 one week before anti-PD1 (B), or anti-PD1 one week before ABI-009 (C). Results: Overall, all treatments were well tolerated with no significant body weight loss in any group. All treatment groups showed significant antitumor effect and longer survival compared with the saline control. Addition of ABI-009 simultaneously or after anti-PD1 significantly improved tumor growth suppression and survival compared with anti-PD1 alone. Tumor volumes were reduced 35.5% for group A and 44.8% for group C when compared with anti-PD1 alone (p < 0.05). Median survival was 26 days for group A and 26 days for group C vs. 20 days for anti-PD1 alone (p < 0.05). On the other hand, group B failed to significantly improve antitumor effect and survival over anti-PD1 alone. The combination treatment regimen of anti-PD1 given before ABI-009 (group C) was the best schedule among the 3 schedules tested. Conclusions: The combination of ABI-009 and anti-PD1 antibody was well tolerated. Results from this study support the treatment regimens of anti-PD1 immunotherapy, concurrent or followed by ABI-009. Pretreatment with ABI-009 followed by anti-PD1 is not recommended. A phase 1b investigation of safety/efficacy of nivolumab and ABI-009 in patients with advanced sarcoma has been initiated. Citation Format: Shihe Hou, Berta Grigorian, Anita Schmid, Neil Desai. Antitumor activity of ABI-009 (nab-rapamycin) in combination with anti-PD1 antibody in a syngeneic mouse model of B16 melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3856.