Modulating Treatment Outcomes of Patients with Solid Tumors in Immunotherapy Trials: A Drug Interaction Analysis from a Phase 1 Unit.

Concurrent use of medications can modulate the effectiveness of immunotherapy. Although this interaction is well documented for immune checkpoint inhibitors, whether this occurs with new experimental compounds has not been evaluated. A computerized data extraction tool was used to collect clinical data and identify the prescription of a predefined set of medications within 30 days of immunotherapy infusion in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors.

Purpose: Intratumoral injection of Clostridium novyi-NT, lacking alpha toxin, germinates and subsequently replicates in the tumor hypoxic regions, causing cell lysis and inflammation. This phase 1b study investigated the safety and synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors.

Plinabulin following radiation enhances dendritic cell maturation and checkpoint inhibitor retreatment of relapsed/refractory cancers.

Background: Plinabulin exerts immunomodulatory activity through guanine nucleotide exchange factor (GEF)-H1 release from depolymerizing tubulin in the cytoskeleton, leading to dendritic cell (DC) activation. Preclinical studies demonstrated that irradiation potentiates plinabulin-induced DC maturation and, when combined with immune checkpoint inhibitors (ICIs), triggers an abscopal antitumor response via increased tumor-infiltrating DCs and T cells.

Methods: A phase 1 translational study (NCT04902040) of plinabulin plus ICIs after radiation therapy (RT) initiation was conducted in ICI-relapsed/refractory cancers with primary (safety, tolerability, and objective tumor response rate) and secondary (disease control rate [DCR]) endpoints.

A B7H3-targeting antibody-drug conjugate in advanced solid tumors: a phase 1/1b trial.

Antibody-drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies.

Myeloid targeting antibodies PY159 and PY314 for platinum-resistant ovarian cancer.

Background: Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and are associated with worse clinical outcomes in PROC. We evaluated the safety and preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral myeloid cells, and PY314, an antagonist antibody to Triggering receptor expressed on myeloid cells-2 (TREM2) that depletes tumor-associated macrophages, as single agents and in combination with pembrolizumab in subjects with PROC.

Lefitolimod in Combination with Ipilimumab in Patients with Advanced Solid Tumors: A Phase I Trial.

Introduction: TLR9 agonists are immunomodulators that have been of interest for combined use with cancer immunotherapy. TLR9 agonists, such as lefitolimod (MGN1703), significantly increased Th1 response in preclinical models and have demonstrated efficacy in early clinical trials. This trial assessed the safety and preliminary efficacy of the combination of lefitolimod and ipilimumab in patients with advanced solid tumors.

A Phase IB Trial of Selinexor in Combination With Immune Checkpoint Blockade in Patients With Advanced Renal Cell Carcinoma.

Background: Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy.

Methods: NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies.

Preclinical study and parallel phase II trial evaluating antisense STAT3 oligonucleotide and checkpoint blockade for advanced pancreatic, non-small cell lung cancer and mismatch repair-deficient colorectal cancer.

Objective: To evaluate signal transducer and activator of transcription 3 (STAT3) inhibition we conducted a co-clinical trial testing danvatirsen, a STAT3 antisense oligonucleotide (ASO) and checkpoint inhibition in conjunction with preclinical experiments.

Methods And Analysis: Orthotopically implanted pancreatic cancer (pancreatic adenocarcinoma (PDAC)) was treated with STAT3 ASO with immune checkpoint inhibition. Tumour infiltrating immune cell populations were characterised via flow cytometry.

Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial.

Background: Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors.

Phase II study of talazoparib in advanced cancers with BRCA1/2, DNA repair, and PTEN alterations.

Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2.

Therapeutic Role of Synthetic Lethality in -Deficient Malignancies.

AT-rich interaction domain 1A (ARID1A), a mammalian switch/sucrose nonfermenting complex subunit, modulates several cellular processes by regulating chromatin accessibility. It is encoded by , an immunosuppressive gene frequently disrupted in a many tumors, affecting the proliferation, migration, and invasion of cancer cells. Targeting molecular pathways and epigenetic regulation associated with ARID1A loss, such as inhibiting the PI3K/AKT pathway or modulating Wnt/β-catenin signaling, may help suppress tumor growth and progression.

Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228/TAK-228) in Combination with Metformin in Patients with mTOR/AKT/PI3K Pathway Alterations and Advanced Solid Malignancies.

Background: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5'-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors.

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies.

Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.

T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy.

Background: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research.

A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.

Purpose: Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.

A Phase I Trial of Bevacizumab and Temsirolimus in Combination With Valproic Acid in Advanced Solid Tumors.

Background: Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity.

Methods: This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer.

Results: Median age of enrolled patients was 56 years.

Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers.

Purpose: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.

Experimental Design: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC.

A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors.

Background: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1.

Objective: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles.

Patients And Methods: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease.

Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies.

Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival.

Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101).

Purpose: Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma.