Research ArticleClinical Studies
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A Phase I/II Investigation of Safety and Efficacy of Nivolumab and nab-Sirolimus in Patients With a Variety of Tumors With Genetic Mutations in the mTOR Pathway

ERLINDA M. GORDON, NICOLE L. ANGEL, NADEZHDA OMELCHENKO, VICTORIA S. CHUA-ALCALA, ANIA MORADKHANI, DORIS QUON and STEVEN WONG
Anticancer Research May 2023, 43 (5) 1993-2002; DOI: https://doi.org/10.21873/anticanres.16360

Abstract

Background/Aim: Advanced sarcoma has a poor prognosis. Dysregulation of the mammalian target of rapamycin (mTOR) occurs in various types of cancer. We aimed to determine the safety and efficacy of mTOR inhibitor nab-sirolimus when combined with the immune checkpoint inhibitor nivolumab. Patients and Methods: Previously treated patients ≥18 years with confirmed diagnosis of advanced sarcoma or tumor with mutations in the mTOR pathway were treated with 3 mg/kg nivolumab intravenously every 3 weeks; escalating doses of nab-sirolimus at 56, 75 or 100 mg/m2 were administered intravenously on days 8 and 15 beginning in cycle 2. The primary aim was to determine the maximum-tolerated dose; we also determined disease control, objective response, progression-free survival, overall survival, and correlation between response using Immune-related Response Evaluation Criteria for Solid Tumors (irRECIST) versus RECIST v1.1. Results: The maximum-tolerated dose was 100 mg/m2. There were two patients with partial response, 12 with stable disease and 11 with progressive disease. Median progression-free and overall survival were 12 and 47 weeks, respectively. The best responders (partial responses) were patients with undifferentiated pleomorphic sarcoma with loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), tuberous sclerosis complex 2 (TSC2) mutation and estrogen receptor-positive leiomyosarcoma. Treatment-related adverse events of grade 3 or more included thrombocytopenia, oral mucositis, rash, hyperlipidemia and increased serum alanine aminotransferase. Conclusion: The data indicate that (i) treatment with nivolumab plus nab-sirolimus is safe with no unexpected adverse events; (ii) treatment outcome parameters were not improved by combining nivolumab with nab-sirolimus; and (iii) best responders were patients with undifferentiated pleomorphic sarcoma with PTEN loss and TSC2 mutation and estrogen receptor-positive leiomyosarcoma. Future direction in sarcoma research with nab-sirolimus will be biomarker-based (TSC1/2/mTOR, tumor mutational burden/mismatch repair deficiency etc.).

Key Words:

Advanced solid malignancies are most often invariably fatal and innovative treatments are urgently needed. The mammalian or mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase forming the catalytic subunit of mTOR complex 1 (mTORC1) and mTORC2. These complexes are essential for the control of cellular growth, proliferation and survival (1). Specifically, mTORC1 plays a critical role in metabolism by suppressing catabolic pathways such as autophagy and increasing anabolism of proteins, lipids and nucleotides in response to changes in environmental conditions such as high stress or states of hypoxia (1). mTORC2 is primarily involved in cellular proliferation and survival by phosphorylating substrates that are involved in numerous aspects of cytoskeletal remodeling as well as cell migration (1). The most crucial role of mTORC2, however, is that it activates AKT serine/threonine kinase 1 (AKT), which is a major effector of insulin/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling which then acts to inhibit several key substrates including the tuberous sclerosis complex 2 (TSC2), which down-regulates mTORC1 (1). There are many growth factor pathways that converge at TSC. Mutations in TSC1 or TSC2 have been shown to cause hyperactivation of mTORC1 which normally down-regulates autophagy and up-regulates glucose metabolism, nucleotide synthesis and mRNA translation (2).

Rapamycin is an inhibitor of mTOR, which gives it immunosuppressive and anticancer properties (3). Numerous studies have shown that cancer cells significantly up-regulate the PI3K/AKT/mTOR pathway, which makes this pathway an enticing target for anticancer therapies [reviewed in (4)]. Nab-sirolimus is a novel, albumin-bound rapamycin nanoparticle (formerly known as nab-rapamycin and ABI-009) designed to enhance drug delivery to target sites (5). Nab-sirolimus was recently approved as first-line treatment (6) of a rare subtype of soft-tissue sarcoma known as malignant perivascular epithelioid cell tumor (PEComa) (7). The aim of this phase I study was to determine the safety, maximum tolerated dose (MTD) and potential synergistic antitumor activities of nivolumab (8), an immune checkpoint inhibitor, combined with nab-sirolimus in a variety of advanced sarcomas and other tumors with genetic alterations sensitive to mTOR inhibitors.

Patients and Methods

Study design. This was an open-label, single-center, dose-finding phase IB study using a fixed dose of nivolumab and escalating doses of nab-sirolimus given intravenously. Patients were enrolled from September 2017 to July 2021. The study was conducted in accordance with the Declaration of Helsinki and approved by the Western Institutional Review Board (Protocol Code 20151429 on September 8, 2017) for studies involving humans.

The primary endpoint was determination of the MTD of nab-sirolimus when combined with nivolumab. Secondary endpoints included the disease control rate [DCR: complete response (CR) plus partial response (PR) plus stable disease] as determined by local radiological assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (9); the objective response rate (CR plus PR), and progression-free (PFS), and overall (OS) survival. Secondary endpoints also included determination of the median PFS and median OS.

The exploratory endpoint evaluated the correlation between response based on immune-related response criteria (irRECIST) (10) and that based on RECIST v1.1 (9) using Pearson’s coefficient of correlation (11).

Dose-escalation phase I part of the study. The study employed the standard “cohort of three” design (12), wherein three patients were treated at each dose level with expansion to six patients per cohort when dose-limiting toxicity (DLT) was observed in one out of the three initially enrolled patients at each dose level. If no DLT occurred after two doses, escalation to the next dose level was permitted. The MTD was defined as the highest safely tolerated dose at which no more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. Patients in the dose-escalation study were able to continue treatment at their designated dose levels for up to 18 3-week cycles or until significant disease progression or unacceptable toxicity occurred. No intra-patient dose escalation took place.

The dose of nivolumab given was 3 mg/kg intravenously over 30 min q 3 weeks (day 1 of every 21-day cycle) beginning in cycle 1. Nab-sirolimus was administered on days 8 and 15 beginning in cycle 2. Nivolumab was given first based on preclinical findings of increased efficacy when administered before nab-sirolimus (13). Escalating doses of nab-sirolimus were given intravenously over 30 min for 2 out of every 3 weeks starting from 56 mg/m2 (n=3-6); 75 mg/m2 (n=3-6) and 100 mg/m2 (n=3-6).

Note that DLT included colitis, hepatitis, or pneumonitis of grade 3 or more; any grade 1-2 colitis, hepatitis or pneumonitis that recurred, worsened or persisted with oral steroids longer than 14 days; symptoms of adrenal crisis; any grade 4 hematological toxicity; or any non-hematological toxicity of grade 3 or more, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (14). When DLT developed in more than one patient at 56 mg/m2, the dose of nab-sirolimus was de-escalated to 45 mg/m2 and to 30 mg/m2 when a DLT developed at 45 mg/m2.

Expansion phase II part of study. Following dose escalation, an additional 22-28 patients were to receive defined doses of nivolumab and nab-sirolimus at the MTD to assess overall safety and potential efficacy in a greater number of patients. Patients in the expansion phase of the study were able to continue treatment for up to 18 3-week treatment cycles or until significant disease progression or unacceptable toxicity occurred. The study was conducted in compliance with the International Conference on Harmonisation Good Clinical Practices (15).

After three or more treatment cycles, the principal investigator was able to recommend surgical debulking, complete surgical removal or a biopsy. If residual disease was present either by histopathological examination or by computerized tomography (CT) scan/magnetic resonance imaging (MRI), repeat treatment cycles could be given 2-4 weeks after surgery, when the surgical incision had healed, and if the patient had less than grade 1 toxicity.

Treatment was continued in the presence of increased tumor size by CT scan or MRI, indicating progressive disease by RECIST v1.1 (9) when there were no signs or symptoms indicating unequivocal progression, no worsening of Eastern Cooperative Oncology Group (ECOG) score attributable to progressive disease, no tumor growth at critical sites that was life-threatening, when the patient had signed an informed consent form that they were aware of alternative therapies but wished to defer these therapies, or when there was clinical benefit, as determined by the investigator.

Study population. Regarding sample size, 40-50 patients were to be enrolled. Patients who failed to become evaluable for the secondary endpoint with a follow-up CT/MRI were replaced. Tumors with histology of Ewing sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small-cell lung cancer, small-cell lung cancer, urothelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors, were confirmed locally by the institution prior to enrollment.

Patient eligibility

Inclusion criteria. A patient was eligible for inclusion in this study only when all of the following criteria were met:

  • Histologically confirmed diagnosis of Ewing sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urothelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors that were either metastatic or locally advanced and for which surgery was not a recommended option;

  • One or more measurable target lesions by CT scan or MRI, measurable disease by RECIST v1.1, confirmed by investigator;

  • Previous treatment completed after 5 half-lives or ≥28 days prior to enrollment, whichever was shorter;

  • ≥40 kg For those aged 12-17 years, or 18 years or older, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;

  • Blood chemistry levels at screening (obtained ≤14 days prior to enrollment, local laboratory): Total bilirubin ≤1.5×upper limit of normal (ULN) mg/dl, aspartate aminotransferase/alanine aminotransferase ≤2.5×ULN (≤5×ULN if attributable to liver metastases), alkaline phosphatase <3×ULN (or ≥3×ULN when due to bone metastases), serum creatinine ≤1.5×ULN;

  • Blood counts at screening (obtained ≤14 days prior to enrollment, local laboratory): Absolute neutrophil count ≥1.5×109/l, platelet count ≥100,000/mm3 (100×109/l), hemoglobin ≥9 g/dl, serum triglyceride <300 mg/dl, serum cholesterol <350 mg/dl;

  • Males and females of child-bearing age had to agree to use effective contraception 28 days before treatment with study drugs, while on study, and have a negative serum pregnancy test (human chorionic gonadotrophin) result at screening and to agree to have pregnancy testing during the study period, and after the end of treatment with study drugs. A second form of birth control was required even in the case of tubal ligation. Male patients were required to practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study. A second form of birth control was required even in the case of successful vasectomy;

  • Life expectancy of ≥3 months, as determined by the investigator;

  • Ability to understand and provide signed informed consent;

  • Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures.

Exclusion criteria. A patient was not eligible for inclusion in this study when any of the following criteria applied:

  • Known active uncontrolled or symptomatic central nervous system (CNS) metastases. For patients with controlled and asymptomatic CNS metastases, prior treatment for CNS metastases must have been completed ≥28 days (including radiotherapy/surgery) prior to the start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases;

  • Active gastrointestinal bleeding;

  • Uncontrolled pre-existing thyroid abnormality;

  • Uncontrolled serious medical or psychiatric illness;

  • ‘Currently active’ second malignancy, with the exception of patients with non-melanoma skin cancer, carcinoma in situ of the cervix, resected incidental prostate cancer (staged pT2 with Gleason Score ≤6 and postoperative prostate-specific antigen <0.5 ng/ml), or other adequately treated carcinoma in-situ; patients were not considered to have a currently active malignancy when they had completed therapy and were free of disease for ≥1 year;

  • Liver-directed therapy within 2 months of enrollment. Prior treatment with radiotherapy [including radio-labeled spheres or CyberKnife, hepatic arterial embolization (with or without chemotherapy) or cryotherapy/ablation] was allowed when these therapies did not affect the areas of measurable disease being used for this protocol;

  • Infection requiring systemic anti-infective treatment that was completed ≤14 days prior to enrollment (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection);

  • Uncontrolled diabetes mellitus as defined by HbA1c ≥8% despite adequate therapy;

  • Unstable coronary artery disease or myocardial infarction during the preceding 6 months;

  • Receipt of any concomitant antitumor therapy;

  • History of interstitial lung disease, pneumonitis, or pulmonary hypertension;

  • Use of strong inhibitors and inducers of cytochrome P450 3A4 (CYP3A4) in the 14 days prior to receiving the first dose of nab-sirolimus. Additionally, use of any known CYP3A4 substrate 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 nab-sirolimus;

  • Active hepatitis B or hepatitis C;

  • Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks of trial enrollment;

  • Autoimmune disease including rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis and motor neuropathy considered to be of autoimmune origin (e.g. Guillain–Barre syndrome);

  • Systemic immunosuppression, including human immunodeficiency virus positive status with or without acquired immune deficiency syndrome;

  • Skin rash (psoriasis, eczema) affecting ≥25% body surface area;

  • Inflammatory bowel disease (Crohn’s or ulcerative colitis);

  • Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment;

  • Recent history of acute diverticulitis, intraabdominal abscess or gastrointestinal obstruction within 6 months of trial enrollment (known risk factors for bowel perforation);

  • Current, active or previous history of heavy alcohol abuse;

  • Pituitary endocrinopathy;

  • Adrenal insufficiency or excess.

Length of study. The study was expected to take approximately 32 months from the first patient enrolled to last patient follow-up, including approximately 24 months of enrollment, an estimated 6 months of treatment (or until treatment was no longer tolerated) and an end of treatment visit at 4 weeks (±7 days) after the last treatment.

The end of the study was defined as either the date of the last visit of the last patient, or the date of receipt of the last data point from the last patient that was required for primary, secondary, or exploratory analysis, as pre-specified in the protocol.

End of treatment for a patient was defined as the date of the last dose of nivolumab or nab-sirolimus. End of treatment visit for a patient was when safety assessments and procedures were performed after the last treatment, which had to be at least 4 weeks (±7 days) after the last dose of nivolumab or nab-sirolimus.

The follow-up period was the on-study time period after the end of treatment visit. All patients that discontinued the study drug and did not withdraw full consent to participate in the study continued in the follow-up phase for survival and initiation of anticancer therapy. Follow-up took place approximately every 12 weeks (±3 weeks), until death, withdrawal of consent, or study closure, whichever was the earliest. This evaluation may have been made by record review with/without telephone contact.

Statistical considerations

Safety analyses: Demographic and baseline information (e.g., extent of prior therapy) for study patients was tabulated. The number of patients studied for the dose-escalation part of the study was nine, and was 22 for the dose-expansion part.

For the phase I part of the study, the following information was reported for all adverse events observed: Dose level, type (organ affected or laboratory determination, such as absolute neutrophil count), severity [by CTCAE version 4.03 (14) and most extreme abnormal values for laboratory determinations] and relatedness to study treatment. For each dose, the number and percentage of patients experiencing any grade 3, 4, or 5 adverse event were reported, as well as the number and percentage of patients who experienced selected, specific types of adverse event. In addition, the DLTs were summarized by dose level and the MTD was determined.

For the phase I part of the study, the entire treated population (full analysis set) was that analyzed for all safety analyses. Summary tables included the number and percentage of patients with adverse events, serious adverse events, fatal adverse events and other adverse events of interest. Safety was analyzed in all patient groups together (metastatic and locally advanced disease). Frequency tables, graphs, and summary statistics were used for outcome data.

The incidence of all treatment-emergent adverse events were tabulated. Tables of fatal adverse events, serious adverse events, treatment-related adverse events, and adverse events leading to withdrawal from the study drugs were also collected.

For nivolumab and nab-sirolimus exposure, summary statistics were used for the total number of doses, average dose administered, and duration of each treatment.

Efficacy analyses: The disease control rate (CR, PR, SD), objective response rate (ORR), progression free survival (PFS) and overall survival (OS) were assessed by local radiological assessment using RECIST v1.1 (9) and irRECIST (10).

The focus of the study was to estimate the DCR in patients treated with nivolumab and nab-sirolimus. Patients who disease progressed before receiving nab-sirolimus were replaced and were not included in the statistical analysis. The number and percentage of patients achieving response was summarized.

Analysis of other efficacy endpoints, median PFS, and median OS were assessed for all tumor subtypes together.

The number of patients in each category was expected to be small; therefore, median PFS and median OS for these patients were summarized by descriptive statistics.

Exploratory analysis: Response based on RECIST v1.1 (9) was correlated with that based on irRECIST (10) using Pearson’s coefficient of correlation (11).

Results

Demographic information. A total of 34 patients were included in this study. Table I shows the patients enrolled according to sex and race. There were 19 males and 15 females, of whom most (22/34) were White not of Hispanic origin. Table II shows the patients enrolled according to age group and sex. The majority (56%) were young adults between 18 and 39 years of age. Table III shows the histological tumor subtypes of patients enrolled in the study. Most patients (15/34) had osteosarcoma or Ewing sarcoma.

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Table I.

Patients enrolled in the SOC-1701 study, according to race and sex.

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Table II.

Patients enrolled in the SOC-1701 study, according to age group and sex.

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Table III.

Histological cancer subtypes of patients enrolled in the SOC-1701 study.

Summary of safety analysis. Thirty-one out of 34 patients who received at least one dose of nab-sirolimus were evaluable for the safety analysis.

In the phase I part of the study, no DLT occurred. The phase IB part of the study used the standard dose of 3 mg/kg nivolumab every 3 weeks and the MTD dose of 100 mg/m2 nab-sirolimus on days 8 and 15 of each cycle.

AEs by body system. Table IV shows AEs by body system in the phase I part and expanded phase IB part of the study, toxicity grade, and attribution to treatment regimen. Twenty-five out of 31 (80.6%) patients who received at least one dose of nab-sirolimus had at least one treatment-related AE. The number of patients in the dose 3+ expanded phase IB category who had at least one treatment-related AE was 20 out of 25 (80%). Grade 3 adverse events that were considered to be related to nivolumab included increased thyroid-stimulating hormone (3.2%), while grade 3 AEs related to nab-sirolimus included thrombocytopenia (9.7%), oral mucositis (3.2%), increased thyroid-stimulating hormone (3.2%), acute dehydration (3.2%), hypertriglyceridemia (3.2%) and hypophosphatemia (3.2%).

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Table IV.

Adverse events related to study therapy, by grade.

Summary of efficacy analysis. Table V shows the best overall response, PFS and OS data of patients enrolled in the study. Thirty-one out of 34 patients who received at least one treatment cycle and had a follow-up CT scan were evaluable for best overall response, PFS and OS. Three patients did not receive nab-sirolimus.

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Table V.

Efficacy analysis of best overall response, progression-free survival (PFS) and overall survival (OS) (n=31/34).

The best responders (i.e. those with PR) were patients with undifferentiated pleomorphic sarcoma whose tumors had loss of phosphatase and tensin homolog, tuberous sclerosis complex 2 mutation, and leiomyosarcoma whose tumor was estrogen receptor-positive.

As of the data cut-off date, two patients (one with TSC2 and another with TP53 mutation) are still alive after 113 and 104 weeks, two patients with EWSR1–WT1 fusion are still alive after 104 and 106 weeks, and one patient with PIK3CA is still alive after 98 weeks.

Summary of exploratory endpoint analysis

Correlation between RECISTv1.1 and irRECIST: We correlated response according to RECISTv1.1 and irRECIST using Pearson correlation. The Pearson correlation coefficient was 1.00 (p<0.0001), which represents perfect correlation.

Deaths: Table VI shows the list of deaths, Table VII shows the list of patients who withdrew due to an adverse event, and Table VIII shows patients who were lost to follow-up, therefore their survival status is not known. As of the data cut-off date, 23 patients have died from disease progression, eight with disease progression have been lost to follow-up and five patients are still alive. No patient died within 28 days of receiving nab-sirolimus.

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Table VI.

Deaths during the study.

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Table VII.

Patients who withdrew from the study due to adverse event

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Table VIII.

List of patients who were lost to follow-up.

Discussion

Immunotherapy has come of age and immune checkpoint inhibitors in the form of monoclonal antibodies that impede a cancer’s ability to disable and elude the immune system have been approved by the US Food and Drug Administration at a rapid pace (16, 17). The goal of this phase I/II study was to determine if the combination of nivolumab and nab-sirolimus has synergistic activity and can improve the outcome of patients with advanced cancer in whose tumors dysregulation of the mTOR pathway has been determined. Nivolumab, an immune checkpoint inhibitor, is Food and Drug Administration-approved for various clinical indications (8). Nab-sirolimus gained FDA approval for locally advanced unresectable or metastatic malignant PEComa in 2021. In combination with nivolumab, the MTD of nab-sirolimus was 100 mg/m2, which is the same as its MTD, the recommended phase II dose as a single-agent (7, 18).

A review of immune checkpoint inhibitors in advanced sarcoma showed three studies that demonstrated some activity of immunotherapy with or without chemotherapy in previously treated patients with advanced sarcoma. In 2017, the results were published of the SARC028 trial (NCT02301039) using pembrolizumab, a PD1-inhibitor, in 80 patients with previously treated advanced sarcoma (19), wherein seven (8%) patients with soft-tissue sarcoma, particularly undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, had a partial response. Expansion of the SARC028 study showed 22.5% of patients with undifferentiated pleomorphic sarcoma had either CR or PR, and 10% of patients with liposarcoma had a PR (20). In 2018, the results of the ALLIANCE A091401 (NCT02500797) study were published, wherein patients with previously treated advanced sarcoma received either nivolumab alone or plus ipilimumab (an inhibitor of cytotoxic T-lymphocyte-associated protein). Only 5% in the nivolumab-treated cohort had a PR while 13.8% in the combination-treated cohort had a PR (21, 22). The median PFS was 2 and 4 months in the nivolumab and combination cohorts, respectively, which was not different from the results of chemotherapy (23). By indirect comparison, the results of combination nivolumab plus nab-sirolimus showed no difference in the outcome of patients compared with nivolumab alone (21, 22). Perhaps administering nivolumab with nab-sirolimus earlier in the course of the disease when cancer cells are most immunogenic (24) would have a better outcome as previously reported in the SAINT study using the combination of ipilimumab with nivolumab and trabectedin (25). Nevertheless, the study demonstrates the safety of this combination regimen with no additive toxicity. Treatment discontinuations were mainly due to disease progression. Although sirolimus was originally approved as an immunosuppressant (26, 27), there was no indication that nab-sirolimus hampered the efficacy of nivolumab immunotherapy in this study. Furthermore, this study provided insight into the potential efficacy of nab-sirolimus in patients with tumors having TSC2 mutations. Given that mTOR pathway activation is often observed in solid tumors with TSC1- and TSC2-inactivating alterations, TSC1/TSC2 would be a promising therapeutic target for nab-sirolimus. Biomarker analyses from the AMPECT study and a nab-sirolimus expanded access program in patients with advanced malignant PEComa described antitumor activity in a subset of patients. In AMPECT, 89% of patients with pathogenic TSC2-inactivating alterations had a confirmed CR or PR. Likewise, objective responses and stable disease ≥12 weeks were observed in patients with pathogenic TSC1- or TSC2-inactivating alterations.

Conclusion

Taken together, these data indicate that: (i) The primary endpoint of the study was met. That is, nab-sirolimus given at its MTD/RP2D of 100 mg/m2 may be combined with the immune checkpoint inhibitor, nivolumab, given at the standard dose of 3 mg/kg/dose; (ii) the combination nivolumab/nab-sirolimus did not improve treatment outcome parameters when compared historically with nivolumab alone; and (iii) PR in a patient with TSC2-mutated sarcoma parallels existing data that suggest TSC2 mutation is a target for nab-sirolimus. Thus, PRECISION 1, a phase II basket study using nab-sirolimus in patients with TSC1 or TSC2 mutation has been opened and is now enrolling patients (NCT05103358).

Acknowledgements

The Authors are grateful to patients and the staff of the Sarcoma Oncology Research Center for their enthusiasm and dedication to our mission of finding the best treatment options for patients with cancer.

This research was funded by Aadi Bioscience, Inc., Pacific Palisades CA, USA. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the article; or in the decision to publish the results.

Footnotes

  • Author Contributions

    Conceptualization: EMG, DQ and SGW; methodology: EMG and NLA; validation: EMG, DQ and SGW; formal analysis: EMG, VSC, DQ and SGW; investigation: EMG, VSC, DQ and SGW; data curation: EMG, DQ and SGW; writing – NLA, NO, EMG; writing – review and editing: NLA, NO, EMG, VSC, AM, DQ and SGW; supervision: EMG, DQ and SGW; project administration: VSC and AM; funding acquisition: EMG. All Authors have read and agreed to the published version of the article.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received February 27, 2023.
  • Revision received March 10, 2023.
  • Accepted March 15, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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A Phase I/II Investigation of Safety and Efficacy of Nivolumab and nab-Sirolimus in Patients With a Variety of Tumors With Genetic Mutations in the mTOR Pathway
ERLINDA M. GORDON, NICOLE L. ANGEL, NADEZHDA OMELCHENKO, VICTORIA S. CHUA-ALCALA, ANIA MORADKHANI, DORIS QUON, STEVEN WONG
Anticancer Research May 2023, 43 (5) 1993-2002; DOI: 10.21873/anticanres.16360
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