samotolisib (LY3023414) / Eli Lilly - LARVOL DELTA

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=1376 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=2316 ➔ 1376 | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Jun 2025 ➔ Mar 2025

Biomarker • Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

A Study of LY2835219 (Abemaciclib) in Combination With Therapies for Breast Cancer That Has Spread (clinicaltrials.gov) - P1 | N=198 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • CDK6 • HER-2

DNA-dependent protein kinase inhibitors PI-103 and samotolisib augment CRISPR/Cas9 knock-in efficiency in human T cells. (PubMed, Cytotherapy) - "In addition to the previously reported DNA-dependent protein kinase (DNA-PK) inhibitor M3814, we demonstrated that PI-103 and samotolisib markedly increase KI efficiency in a process that is good manufacturing process (GMP)-compatible. Importantly, samotolisib enabled the generation of a potent T-cell product, having no negative impact on T-cell viability, phenotype, expansion, effector function, and tumor control. Overall, we conclude that our GMP-compatible CRISPR/Cas9 protocol comprising samotolisib to augment TCR KI efficiency is suitable for the generation of genetically modified T cells for clinical use."

IO biomarker • Journal • Gene Therapies • Oncology • Solid Tumor

Abemaciclib in combination with therapies for patients with metastatic breast cancer: a phase 1b study. (PubMed, Front Oncol) - "Nineteen patients in Part E received abemaciclib (150 mg, n=15; 200 mg, n=4) with exemestane + everolimus, 24 patients in Part F received abemaciclib (150 mg, n=18; 200 mg, n=6) with trastuzumab, 12 patients in Part G received 150 mg abemaciclib with fulvestrant + LY3023414 (100 mg, n=7; 150 mg, n=5), and four patients in Part H received abemaciclib (100 mg) with trastuzumab + pertuzumab (with prophylactic loperamide). The objective response rates for patients with measurable disease were 46.2%, 10.0%, 66.7%, and 25.0% in Parts E-H, respectively. A recommended Phase 2 dose was not established for Parts E, G, and H at the dose levels evaluated, and was determined to be 150 mg Q12H in Part F. Overall, our results demonstrate safety profiles consistent with those previously established for abemaciclib and provide preliminary data for these combination therapies in the treatment of HR+, HER2- or HER2+ MBC."

Journal • P1 data • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • HER-2

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2027 ➔ Jun 2025 | Trial primary completion date: Sep 2027 ➔ Jun 2025

Biomarker • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - P2 | N=18 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Oct 2025 ➔ Dec 2024

Biomarker • Trial completion • Trial completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • PTEN • TSC1 • TSC2

Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - P2 | N=18 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2024 ➔ Oct 2025

Biomarker • Trial completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • PTEN • TSC1 • TSC2

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=2316 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Malignant Glioma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • BRAF

RESOLVE: Abemaciclib + Letrozole +/- Metformin or Zotatifin in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov) - P2 | N=130 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2029 ➔ Aug 2030 | Trial primary completion date: Aug 2026 ➔ Aug 2027

Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ER

Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D. (PubMed, JCO Precis Oncol) - "This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice."

Journal • P2 data • Brain Cancer • CNS Tumor • Glioma • Mucositis • Oncology • Osteosarcoma • Pediatrics • Pneumonia • Sarcoma • Solid Tumor • PIK3CA • PTEN

Efficacy and safety of interventions for metastatic castration resistant prostate cancer (mCRPC) patients progressing on androgen receptor-axis-targeted (ARAT) therapy: a systematic literature review. (PubMed, Curr Med Res Opin) - "A total of 16 trials evaluated ARAT based therapies, 7 trials evaluated taxane-based treatments, 10 trials evaluated PARP inhibitors, 8 trials evaluated immunotherapies, and 8 trials evaluated other therapies (i.e. cabozantinib, mitoxantrone, radium-223, 177[Lu-177]-PNT2002, 177Lu-PSMA-617, samotolisib)...Conversely, agents such as taxane-based chemotherapy (e.g. cabazitaxel) and radionuclide therapy provide the most value in this patient population. Further research is needed to explore new therapies in this disease area and to optimize existing treatment strategies with more effective combination therapies."

Journal • Metastases • Review • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway. (PubMed, Mol Oncol) - "Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer."

Journal • Breast Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • HER-2 • PIK3CA • PTEN

RESOLVE: Abemaciclib + Letrozole +/- Metformin or Zotatifin in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov) - P2 | N=130 | Recruiting | Sponsor: Dana-Farber Cancer Institute | N=60 ➔ 130 | Trial completion date: May 2026 ➔ Aug 2029 | Trial primary completion date: May 2024 ➔ Aug 2026

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ER

A phase 1/2, open-label, randomized, dose-finding and dose expansion study of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC). (ASCO 2024) - P1/2 | "A Phase 2 trial in 129 patients with mCRPC who progressed on abiraterone demonstrated improved median radiographic progression-free survival (rPFS) when samotolisib, a dual PI3K-mTOR inhibitor, was added to enzalutamide. Secondary endpoints include rPFS rates at 9 and 12 months, overall rPFS, prostate-specific antigen response of ≥50% decrease from baseline at 4, 8, 12, and 16 weeks, overall response rate, duration of response, clinical benefit rate, overall survival rate at 18 and 24 months, and safety. The trial is currently open for enrollment (NCT06190899)."

Clinical • Combination therapy • Metastases • P1/2 data • Diabetes • Genito-urinary Cancer • Metabolic Disorders • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

A phase 1/2, open-label, randomized, dose-finding and dose expansion study of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC) (AACR 2024) - P1/2 | "A Phase 2 trial in 129 patients with mCRPC who progressed on abiraterone demonstrated improved median radiographic progression-free survival (rPFS) when samotolisib, a dual PI3K-mTOR inhibitor, was added to enzalutamide. Secondary endpoints include rPFS rates at 9 and 12 months, overall rPFS, prostate-specific antigen response of ≥50% decrease from baseline at 4, 8, 12, and 16 weeks, overall response rate, duration of response, clinical benefit rate, overall survival rate at 18 and 24 months, and safety. The trial is currently open for enrollment."

Clinical • Combination therapy • Metastases • P1/2 data • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

A Study of LY2835219 (Abemaciclib) in Combination With Therapies for Breast Cancer That Has Spread (clinicaltrials.gov) - P1 | N=198 | Active, not recruiting | Sponsor: Eli Lilly and Company | Phase classification: P1b ➔ P1

Combination therapy • Metastases • Phase classification • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • CDK6 • HER-2

Preclinical Models of Anal Cancer Combined-Modality Therapy. (PubMed, J Surg Res) - "We have provided proof of concept for two preclinical anal cancer treatment models that allow for the future testing of novel therapies for anal cancer."

Journal • Preclinical • Anal Carcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • PIK3CA

Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: A randomized controlled trial. (PubMed, Cancer Med) - "In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC."

Journal • Metastases • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDK4 • TGFB1

A Study of LY2835219 (Abemaciclib) in Combination With Therapies for Breast Cancer That Has Spread (clinicaltrials.gov) - P1b | N=198 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Sep 2023 ➔ Dec 2024

Combination therapy • Metastases • Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • CDK6 • HER-2

Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - P2 | N=18 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Sep 2024 ➔ Sep 2023

Biomarker • Metastases • Trial primary completion date • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Gastrointestinal Cancer • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Medulloblastoma • Nephrology • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • TSC1 • TSC2

ExIST: LY3023414 and Prexasertib in Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - P2 | N=10 | Completed | Sponsor: Baylor Research Institute | Active, not recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Nov 2022

Metastases • Trial completion • Trial completion date • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER

Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial) (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Metastases • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Ewing Sarcoma • Gastrointestinal Cancer • Germ Cell Tumors • Glioma • Hematological Malignancies • Hepatoblastoma • Hepatology • Langerhans Cell Histiocytosis • Lymphoma • Medulloblastoma • Nephrology • Neuroblastoma • Neuroendocrine Tumor • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Pediatrics • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Wilms Tumor • TSC1 • TSC2

Phase 1b/2 Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer. (PubMed, Clin Cancer Res) - P2 | "Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone and this may be enriched in patients with PTEN intact and no AR-v7."

Journal • P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • mTOR • PTEN

Dual inhibition of RAS and the IGF2/IGF1R pathways: a potential targeting strategy for RAS-mutated embryonal rhabdomyosarcoma (AACR 2023) - "Combination of comprehensive genomic profiling and a laboratory-based 3D micro-cancer model using the patient’s own tumor is an effective way to determine drug efficacy. Targeting RAS pathway by single agents, increases the possibility of resistance. Dual targeting of downstream pathways by MEK and PI3K pathway inhibition is highly toxic, and the clinical usage of this combination is limited."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • IGF1R • IGF2 • KRAS • mTOR

ExIST: LY3023414 and Prexasertib in Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - P2 | N=10 | Active, not recruiting | Sponsor: Baylor Research Institute | Trial completion date: Dec 2022 ➔ Dec 2023

Metastases • Trial completion date • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER