Monica M Mita

• MD
• Managing Director at Cedars-Sinai Medical Center

Background Abequolixron is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. The binding of ApoE to its receptor LRP8 robustly inhibits angiogenesis and depletes myeloid-derived suppressor cells (MDSCs), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to bot...

3102 Background: KB-0742 is a potent, and selective, oral inhibitor of CDK9 being evaluated in a phase I/II study in patients with transcriptionally addicted advanced solid tumors (NCT04718675). Interim data from the first 4 dose levels were presented previously noting manageable safety (MTD not reached), a 24-hour plasma half-life, linear PK, CDK9...

Background LNS8801 is an agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 results in increased melanocytic differentiation, reduced c-Myc protein levels, inhibition of proliferation, and enhancement of immune recognition of cancer cells. In the first-in-human study, LNS8801 was safe and tolerable alone and in combination with pemb...

9543 Background: LNS8801 is an oral, selective, small molecule agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 treatment results in increased melanocytic differentiation, reduced c-Myc protein levels in cancer cells, inhibition of proliferation, suppression of invasion, and enhancement of immune recognition. In preclinical models...

TPS2664 Background: V-domain Ig Suppressor of T-cell Activation (VISTA), is an immune checkpoint regulator found on tumor, myeloid, and other immune cells. Its presence has been shown to enhance tumor growth, create an immunosuppressive microenvironment, and may potentially contribute to developing resistance to anti-CTLA-4 and anti-PD-1/PD-L1 ther...

1054 Background: KAT6A and KAT6B regulate gene transcription via acetylation of histone H3K23 and their dysregulation drives lineage-specific gene expression in cancer. We report dose escalation data from the first-in-human phase 1 (Part 1A and 1B; NCT04606446) study of the KAT6-selective inhibitor PF-07248144. Methods: Part 1A (monotherapy dose es...

PARP (poly(ADP-ribose) polymerase) inhibitors represent a novel class of anti-cancer therapy; they take advantage of synthetic lethality and induce cell death by exploiting a defect in DNA repair. This class of medication was initially evaluated in patients with BRCA-associated tumors, but efficacy was also demonstrated in other populations. Since...

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of...

Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral p...

The tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence of an activated RAS pathway in several solid tumor types. However, the mechanisms of selective anticancer efficacy of the reovirus-based formulation for cancer therapy (Reolysin, pelareorep) have not been...

Background: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed Pharmacodynamic and preliminary anti-tumour activity. Methods: In part 1, pati...

Intoduction: Soft tissue sarcomas (STS) encompass a group of rare tumors arising from mesenchymal tissue. Traditionally, anthracycline-based chemotherapy, with doxorubicin, is the main treatment for advanced STS. Areas covered: Aldoxorubicin is a doxorubicin derivative containing a carboxylic hydrazone and serves as a prodrug of doxorubicin. It cov...

Mammalian target of rapamycin (mTOR) is a clinically validated target in the treatment of cancer. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2 which regulate cell growth, metabolism, proliferation, and survival. Rapamycin analogues target only the mTORC1 complex but do not affect the mTORC2 complex, which is an important driver...

Wnt signaling is an evolutionarily conserved pathway that controls cell-to-cell interactions during embryogenesis. In adults, Wnt signaling plays a role in tissue homeostasis in almost every organ system. Aberrations within this pathway are implicated in a spectrum of human diseases. A variety of perturbations have been described in both solid and...

2577 Background: CC-90003 is an irreversible inhibitor of ERK 1/2 with potent anti-proliferative activity in KRAS and BRAF mutant tumor models. We conducted a first-in-human study of CC-90003 in patients with RAS or BRAF mutant tumors. Methods: Patients received escalating doses of oral CC-90003 on a 21/28 day cycle. Standard safety (adverse events...

PurposeA phase I two-period two sequence cross-over study compared the bioavailability of two pimasertib (MSC1936369B/AS703026) formulations (capsule versus tablet) in advanced cancer patients. Methods Patients with advanced solid tumors were randomized to one of two treatment sequences utilizing pimasertib tablet (test; 3 × 20 mg, PO QD) and capsu...

Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A...

Background CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types. Objective The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary c...

Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune re...

Background LIV-1, a multispan transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells (Sussman 2014). It has been associated with lymph node involvement and linked with malignant progression to metastasis (Manning 1994). SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monome...

Metformin has been used for nearly a century to treat type 2 diabetes mellitus. Epidemiologic studies first identified the association between metformin and reduced risk of several cancers. The anticancer mechanisms of metformin involve both indirect or insulin-dependent pathways and direct or insulin-independent pathways. Preclinical studies have...

Purpose: First-in-human phase 1 trial to determine the safety, pharmacokinetics, and anti-tumor activity of BIND-014, a novel, tumor PSMA-targeted nanoparticle containing docetaxel. Experimental design: Patients with advanced solid tumors received BIND-014 every three weeks (n=28) or weekly (n=27) with dose levels ranging from 3.5 to 75 mg/m2 an...

Rapamycin and its analogs, known as “rapalogs,” are a class of drugs that inhibit the mammalian target of rapamycin (mTOR), which acts downstream of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway. Activating mutations along this pathway are known to be drivers of certain malignancies. While the use of rapamycin has been limited...

Background: BIND-014 is a novel, prostate-specific membrane antigen (PSMA) targeted AccurinTM (polymeric nanoparticle) containing docetaxel. PSMA is expressed on prostate cancer cells and on vasculature of many solid tumors. In a phase 1 study in patients with solid tumors BIND-014 was generally well-tolerated and displayed anti-tumor activity acro...

Background KHK2866 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed at heparin-binding epidermal growth factor-like growth factor (HB-EGF). Objective To determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, potential immunogenicity, and preliminary clinical efficacy of KHK286...

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The...

Background: BIND-014 is a novel, prostate-specific membrane antigen (PSMA)targeted, polymeric nanoparticle-containing docetaxel (DTXL). PSMA is expressed on prostate cancer cells and on vasculature of non-prostate solid tumors. The PK profile of BIND-014 is characterized by reduced CL and V(D). These characteristics together with PSMA targeting, po...

Alisertib (MLN8237) is an investigational, oral, smallmolecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized t...

Background First identified as an estrogen-inducible gene in a breast cancer cell line, LIV-1 is a multispan transmembrane protein of the solute-carrier family 39 with putative zinc transporter and metalloproteinase activity. As a downstream target of STAT3, it promotes the epithelial-to-mesenchymal transition that is important in the malignant pro...

To evaluate the maximum tolerated dose, safety profile, pharmacokinetics, and pharmacodynamics of pegaspargase (PEG-ASP) in combination with gemcitabine in patients with advanced metastatic solid tumors and lymphoma. We conducted a multicenter, open label, nonrandomized, Phase 1 dose escalation study designed to evaluate up to 10 cohorts of patient...

Elevated expression of the anti-apoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mammalian target of rapamycin (mTOR) inhibitor...

The immune modulatory oligonucleotide IMO-2055 (EMD 1201081) is a phosphorothioate oligodeoxynucleotide agonist of Toll-like receptor 9. In preclinical studies, IMO-2055 was shown to activate natural killer cells and to support the antitumor activity of monoclonal antibodies. This phase 1b, open-label, 3 + 3 dose-escalation trial was performed to d...

This book describes the challenges involved in developing mTOR inhibitors for cancer treatment, starting with an in-depth examination of their molecular mechanism of action, with emphasis on the class side-effects, efficacy and mechanisms of resistance, as well as on promising novel directions for their development, including novel compounds and ra...

Introduction Aldoxorubicin, a prodrug of doxorubicin, binds covalently to serum albumin in the bloodstream and accumulates in tumors. Aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity. Purpose This study fully evaluated the pharmacokinetic profile of aldoxorubicin (serum and...

Purpose: Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel. Methods: Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m(2) on...

Background: Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate adenocarcinomas and in non-prostatic tumor neovasculature. As a novel target for therapeutic approaches, the distribution pattern of PSMA in primary and metastatic tumors is of significant interest. In this study we addressed the cellu...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: BIND-014 is a novel, targeted, polymeric nanoparticle (NP) containing docetaxel (DTXL). BIND-014 is targeted to prostate-specific membrane antigen (PSMA), a tumor antigen expressed on prostate cancer cells and on the neovasculature of many non-prostate solid tumors....

Aim: To investigate safety and efficacy in four expansion cohorts treated with the combination of PIM and SAR. Methods: The recommended phase 2 dose (RP2D) for the combination of PIM and SAR has previously been defined in a dose escalation part of the same trial as 60 mg and 70 mg QD, respectively. Inclusion criteria included ECOG PS 0-1, and in th...

We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the c...

Introduction: Cabazitaxel is a second-generation taxane with in vivo activity against taxane-sensitive and -resistant tumor cell lines and tumor xenografts. Cabazitaxel/cisplatin have therapeutic synergism in tumor-bearing mice, providing a rationale for assessing this combination in patients with solid tumors. Methods: The primary objectives of...

The development of wild-type, unmodified Type 3 Dearing strain reovirus as an anticancer agent has currently expanded to 32 clinical trials (both completed and ongoing) involving reovirus in the treatment of cancer. It has been more than 30 years since the potential of reovirus as an anticancer agent was first identified in studies that demonstrate...

Purpose: Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose...

We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the c...

Mucositis may limit the therapeutic window for mammalian target of rapamycin inhibitor-based combination therapy, necessitating treatment interruptions and/or dose reductions. Optimizing treatment or prophylactic interventions for mucositis will enable patients to continue effective treatment while maintaining good quality of life.

Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones describe...

Background: Iniparib (I) is a novel anticancer agent initially thought to be a poly (ADP-ribose) polymerase (PARP) inhibitor. Recent preclinical data suggest that iniparib does not inhibit PARP at pharmacologically-relevant concentrations. The initial Phase 1 did not identify any dose limiting toxicity (DLT) and the dose of 5.6 mg/kg used in furthe...

Background: REOLYSIN is a unique, dearing strain oncolytic live virus which has demonstrated the ability to replicate in tumor cells with an activated RAS pathway. It has synergistic antitumor activity in combination with chemotherapy in both preclinical and clinical studies. Based on the promising activity of the combination of REOLYSIN with P/C i...

Introduction: PIK3CA and PTEN are among the top five most frequently mutated genes in breast cancer. Activating mutation of PIK3CA or loss of function mutation in PTEN leads to constitutive activation of AKT and mTOR driving multiple downstream metabolic and proliferative pathways important to oncogenesis. There is also cross-talk between the PI3K/...

Introduction Effective therapies after treatment failure with anthracyclines and taxanes are needed for patients with metastatic breast cancer. Dinaciclib (MK-7965, formerly SCH727965), a small-molecule cyclin-dependent kinase inhibitor, has demonstrated antitumor activity in phase 1 studies with solid-tumor patients. This phase 2 trial was designe...

BIIB021 is the first oral, synthetic, non-geldanamycin based HSP90 inhibitor that showed activity in pre-clinical models at low nanomolar concentrations. We performed a Phase 1 trial of BIIB021 administered to subjects with advanced solid tumors. Sixty patients received BIIB021 capsules orally on Days 1, 4, 8, 11, 15, and 18 of each course in Sched...

Patient outcomes remain poor for advanced or metastatic soft tissue sarcomas (STS) and bone sarcomas despite a growing number of clinical trials involving single- and multi-agent chemotherapy. mTOR is an intracellular kinase that plays a central role in regulating cell growth, metabolism, survival and proliferation. mTOR inhibitors including temsir...

Background: Autophagy is a cellular process that generates energy to assure cell survival in response to insults such as hypoxia, nutrient deprivation or cytotoxic mediators. Autophagy contributes to cancer cell survival as well as drug resistance. Several anticancer agents, including Vorinostat (V) are reported to induce autophagy as a cytoprotect...

Background: BIND-014 is a novel, targeted, polymeric nanoparticle (NP) containing docetaxel (DTXL). BIND-014 is targeted to prostate-specific membrane antigen (PSMA), a tumor antigen expressed on prostate cancer cells and on the neovasculature of many non-prostate solid tumors. In preclinical studies, BIND-014 exhibited pharmacological properties s...

Aurora kinase inhibitors (AKIs) are a class of antimitotic, small-molecule anticancer agents. MSC1992371A is an AKI being evaluated for the treatment of patients with solid tumors. This phase I, open-label, dose-escalation study determined the maximum tolerated dose (MTD) of MSC1992371A in different dosing schedules in patients with locally advance...

Purpose: A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles. Patients and methods: Patients with advanced solid tumors received 1-hour...

Aims: This phase I dose-escalation study was designed to evaluate the combination of the mammalian target of rapamycin inhibitor ridaforolimus with the vascular endothelial growth factor inhibitor bevacizumab. Materials and methods: Seventeen adult patients with refractory advanced solid tumours received oral ridaforolimus (30 or 40 mg) once dai...

Purpose: Panobinostat, a pan-deacetylase inhibitor, is a promising anti-cancer agent that increases acetylation of proteins associated with growth and survival pathways of malignant cells. The primary objective of this phase I dose-escalation study was to determine the maximum tolerated dose (MTD) of intravenous (i.v.) panobinostat administered on...

Introduction: Vascular-disrupting agents (VDAs) are a new class of oncology drugs, which specifically target established tumor neovasculature and have a relatively low toxicity profile. VDAs generally have non-overlapping side effects when concomitantly used with conventional cytotoxics. Several members of the VDA class have recently progressed th...

Background Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral r...

The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel demonstrated li...

Purpose: Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs). Methods:...

Purpose: Dinaciclib, a selective inhibitor of cyclin-dependent kinase (CDK) 1, CDK2, CDK5, and CDK9, is metabolized via CYP3A4. Aprepitant, a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, is an inhibitor and inducer of CYP3A4. We conducted a randomized, crossover study to investigate the effects o...

Purpose Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in p...

A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m(2) (1.1 MBq) of (14) C-radiolabeled patupilone at cycle 1 as a 20-minute i...

This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. Patients with treatment-refractory advanced solid tumors wer...

This phase I dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics (PDs), and preliminary antitumor activity of BGT226, a potent, oral dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin inhibitor. Fifty-seven patients with advanced solid tumors received BGT226 2.5-125 mg...

162 Background: Cabazitaxel (Cbz) is a novel taxane with broad in vivo efficacy in taxane-sensitive and -resistant tumors. Clinical activity of Cbz was confirmed in the Phase III TROPIC trial ( NCT00417079 ); Cbz significantly improved overall survival compared with mitoxantrone in patients (pts) with metastatic castration-resistant prostate cancer...

As part of a phase 1 dose-escalation trial, the pharmacodynamic activity of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus was assessed in multiple tissues by measuring levels of phosphorylated 4E binding protein-1 (p-4E-BP1) or S6, two downstream markers of mTOR activity. 32 patients (pts) were dosed intravenously with ridaforoli...

Background: E7016 is an orally bioavailable, nicotinamide mimetic PARP1 and PARP2 inhibitor. E7016 was shown to enhance the cytotoxic effect of the alkylating agent temozolomide (TMZ) in vivo through inhibition of PARP-mediated DNA repair. This phase I study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxities (DLTs),...

s: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA Purpose: ATI-1123, a novel nanoparticle docetaxel liposomal formulation, is being investigated in patients (pts) with advanced solid malignancies. ATI-1123 is expected to reduce hypersensitivity reactions, have a broader therap...

Background: Alisertib is an investigational, oral, selective AAK inhibitor that has shown antitumor activity in both the PIC and enteric-coated tablet formulations in previously reported clinical trials. A prototype OS formulation of alisertib has been developed for patient populations unable to swallow solid dosage forms (e.g. pediatric patients,...

s: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA Purpose: REOLYSIN® (Reovirus serotype 3) is a Dearing strain, naturally occurring ubiquitous human reovirus. In transformed cells with activated RAS pathway, this reovirus causes preferential lysis due to the inhibition of RNA-...

s: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA Background: Pancreatic cancer (Pca) continues to have a dismal prognosis and very little progress has been made in finding new efficacious treatments. Oncolytic viruses have demonstrated cytotoxic effect in several tumor xenogr...

Background: ATI-1123 is a novel liposomal docetaxel (D) formulation utilizing human serum albumin that facilitates tumor targeting. It was hypothesized that liposomal D formulations may reduce hypersensitivity reactions, eliminate premedication requirements, have a broader therapeutic index, and enhance systemic D exposure. This study assessed the...

Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced...