iSTAR: Phase 1b Trial of Idasanutlin and Selinexor Therapy For Children With Progressive/Relapsed Atypical Teratoid Rhabdoid Tumors, Extra-CNS Malignant Rhabdoid Tumors Or Synchronous/Metachronous Rhabdoid Tumors

iSTAR is an open-label, multi-center, phase 1b study of oral XPO1 inhibitor selinexor and oral MDM2 inhibitor idasanutlin in children with progressive or recurrent atypical teratoid/rhabdoid tumors (AT/RT), malignant rhabdoid tumors (MRT) and synchronous/metachronous rhabdoid tumors.
Primary Objectives
* To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of combination treatment with oral idasanutlin and selinexor in children with recurrent or progressive AT/RT or MRT.
* To characterize the plasma pharmacokinetics of oral idasanutlin and selinexor in children with recurrent or progressive AT/RT or MRT, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability.
Secondary Objectives
* Evaluate safety of the combination treatment with oral idasanutlin and selinexor in children
* Evaluate efficacy of the combination treatment of idasanutlin and selinexor as measured by objective response (partial response [PR] or complete response [CR]) rate separately in progressive/relapsed AT/RT and progressive/relapsed MRT
* Estimate progression-free and overall-survival separately in progressive/relapsed AT/RT and progressive/relapsed MRT

Start Date01 Mar 2024

Sponsor / Collaborator

St. Jude Children's Research Hospital, Inc.

NCT04029688

/ TerminatedPhase 1/2

A Phase I/II, Multicenter, Open-Label, Multi-Arm Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Activity of Idasanutlin in Combination With Either Chemotherapy or Venetoclax in the Treatment of Pediatric and Young Adult Patients With Relapsed/Refractory Acute Leukemias or Solid Tumors

This is a Phase I/II, multicenter, open-label, multi-arm study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin, administered as a single agent or in combination with chemotherapy or venetoclax, in pediatric and young adult participants with acute leukemias or solid tumors.
This study is divided into three parts: Part 1 will begin with dose escalation of idasanutlin as a single agent in pediatric participants with relapsed or refractory solid tumors to identify the maximum tolerated dose (MTD)/maximum administered dose (MAD) and to characterize dose-limiting toxicities (DLTs). Following MTD/MAD identification, three separate safety run-in cohorts in neuroblastoma, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) will be conducted to identify the recommended Phase 2 dose (RP2D) of idasanutlin in each combination, with chemotherapy or venetoclax. Part 2 will evaluate the safety and early efficacy of idasanutlin in combination with chemotherapy or venetoclax in newly enrolled pediatric and young adult participants in neuroblastoma, AML,and ALL cohorts at idasanutlin RP2D. Part 3 will potentially be conducted as an additional expansion phase of the idasanutlin combination cohorts in neuroblastoma, AML, or ALL for further response and safety assessment.

Start Date27 Jan 2020

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

NCT03850535

/ TerminatedPhase 1/2

A Phase Ib/II Study Evaluating the Safety and Efficacy of Idasanutlin in Combination With Cytarabine and Daunorubicin in Patients Newly Diagnosed With Acute Myeloid Leukemia (AML) and the Safety and Efficacy of Idasanutlin in the Maintenance of First AML Complete Remission

This Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, efficacy, and pharmacokinetics of idasanutlin when it is given in combination with cytarabine and daunorubicin in induction, in combination with cytarabine in consolidation, and as a single agent in maintenance for treating participants with acute myeloid leukemia (AML).

Start Date25 Mar 2019

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with Idasanutlin

100 Translational Medicine associated with Idasanutlin

100 Patents (Medical) associated with Idasanutlin

203

Literatures (Medical) associated with Idasanutlin

22 May 2025·BLOOD

A CEBPB/IL-1β/TNF-α feedback loop drives drug resistance to venetoclax and MDM2 inhibitors in monocytic leukemia

Article

Author: Savoy, Lindsey ; Kenna, Isabel ; McWeeney, Shannon K. ; Kurtz, Stephen E. ; Agarwal, Anupriya ; Barton, Michelle ; Lin, Hsin-Yun ; Kaempf, Andy ; Druker, Brian J. ; Ryabinin, Peter ; Köhnke, Thomas ; Johnson, Kara ; Chang, Bill H. ; Wang, Anthony ; Liu, Tingting ; Gosline, Sara J. C. ; Eide, Christopher A. ; Long, Nicola ; Chen, Reid ; Streltsova, Anastatia ; Allen, Basil ; Tognon, Cristina ; Tyner, Jeffrey W. ; Searles, Robert ; Majeti, Ravindra ; Zhang, Haijiao ; Carlos, Amy ; Bottomly, Daniel ; Martin, Emma ; Piehowski, Paul D.

Abstrat:

MDM2 inhibitors are promising therapeutics for acute myeloid leukemia (AML) with wild-type TP53. Through an integrated analysis of functional genomic data from primary patient samples, we found that an MDM2 inhibitor, idasanutlin, like venetoclax, is ineffective against monocytic leukemia (French-American-British [FAB] subtype M4/M5). To dissect the underlying resistance mechanisms, we explored both intrinsic and extrinsic factors. We found that monocytic leukemia cells express elevated levels of CEBPB, which promote monocytic differentiation, suppress CASP3 and CASP6, and upregulate MCL1, BCL2A1, and the interleukin (IL-1)/tumor necrosis factor alpha (TNF-α)/NF-κB pathway members, thereby conferring drug resistance to a broad range of MDM2 inhibitors, BH3 mimetics, and venetoclax combinations. In addition, aberrant monocytes in M4/M5 leukemia produce elevated levels of IL-1 and TNF-α, which promote monocytic differentiation and upregulate inflammatory cytokines and receptors, thereby extrinsically protecting leukemia blasts from venetoclax and MDM2 inhibition. Interestingly, IL-1β and TNF-α only increase CEBPB levels and protect M4/M5 cells from these drugs but not M0/M1 leukemia cells. Treatment with venetoclax and idasanutlin induces compensatory upregulation of CEBPB and the IL-1/TNF-α/NF-κB pathway independent of the FAB subtype, indicating drug-induced compensatory protection mechanisms. The combination of venetoclax or idasanutlin with inhibitors that block the IL-1/TNF-α pathway demonstrates synergistic cytotoxicity in M4/M5 AML. As such, we uncovered a targetable positive feedback loop that involves CEBPB, IL-1/TNF-α, and monocyte differentiation in M4/M5 leukemia and promotes both intrinsic and extrinsic drug resistance and drug-induced protection against venetoclax and MDM2 inhibitors.

01 Dec 2024·LEUKEMIA

Managing the unmanageable: evidence-driven approaches to real-world patient prototypes of TP53-mutant myelodysplastic neoplasms and acute myeloid leukemia

Review

Author: Patel, Shyam A ; Patel, Shyam A.

Patients with TP53 aberrations comprise the highest risk subset of all myeloid malignancies. The managerial conundrum of TP53-mutant myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) stems from refractoriness to or relapse after conventional chemotherapy, as well as the limited translational success of investigational therapies targeting TP53-mutant cells. Thus far, no targeted therapies have been commercially approved for this mutational subset. As a result, management plans for patients with TP53-mutant MDS and AML are often driven by clinical judgment and/or physician preference rather than consensus guidelines backed by a rigorous evidence basis. This clinical case-based, evidence-driven review highlights the most salient data that guides the management of commonly encountered patient prototypes. This review discusses the therapeutic menu of first-line options that derive from multi-institutional experiences as well as from disease-centric consortia and discusses how these first-line options can be optimally tailored to heterogeneous groups of patients. The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents - eprenetapopt, magrolimab, sabatolimab, and idasanutlin - and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025.

01 Dec 2024·INVESTIGATIONAL NEW DRUGS

Targeting MDM2-mediated suppression of p53 with idasanutlin: a promising therapeutic approach for acute lymphoblastic leukemia

Article

Author: Gungordu, Seyda ; Aptullahoglu, Erhan

Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53. Reactivation of p53, which is encoded from the wild type TP53 but lost its function for several reasons, is an attractive therapeutic approach in cancer treatment. p53 can be activated in a non-genotoxic manner by targeting its primary repressor, the MDM2 protein. Clinical trials involving MDM2 inhibitors are currently being conducted in a growing body of investigation, reflecting of the interest in incorporating these treatments into cancer treatment strategies. Early-phase clinical trials have demonstrated the promise of idasanutlin (RG7388), one of the developed compounds. It is a second-generation MDM2-p53 binding antagonist with enhanced potency, selectivity, and bioavailability. The aim of this study is to evaluate the efficacy of RG7388 as a therapeutic strategy for ALL and to investigate its potential impact on improving treatment outcomes for high-risk patients. RG7388 potently decreased the viability in five out of six ALL cell lines with diverse TP53 mutation profiles, whereas only one cell line exhibited high resistance. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic and extrinsic pathways of apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.

News (Medical) associated with Idasanutlin

25 Sep 2023

·synapse.patsnap.com

New approach to cancer treatment-MDM2 inhibitors

MDM2 is a crucial protein found in the human body that plays a significant role in regulating cell growth and division. It acts as a negative regulator of the tumor suppressor protein p53, which is responsible for preventing the formation of cancerous cells. MDM2 binds to p53, inhibiting its activity and promoting its degradation, thereby preventing excessive cell growth and maintaining cellular homeostasis. However, when MDM2 is overexpressed or its function is disrupted, it can lead to the inactivation of p53, allowing uncontrolled cell proliferation and potentially contributing to the development of various cancers. Understanding the role of MDM2 is essential for developing targeted therapies to restore p53 function and combat cancer. MDM2 Competitive LandscapeAccording to the data provided by Patsnap Synapse-Global Drug Intelligence Database: the following figure shows that as of 20 Sep 2023, there are a total of 57 MDM2 drugs worldwide, from 62 organizations, covering 57 indications, and conducting 144 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target. The analysis of the current competitive landscape of target MDM2 reveals that Roche Holding AG, Rain Oncology, Inc., C.H. Boehringer Sohn AG & Co. KG, Kartos Therapeutics, Inc., and Ascentage Pharma Group International Co., Ltd. are the companies growing fastest in this field. These companies have made significant progress in the research and development of drugs targeting MDM2, with Roche Holding AG leading in terms of the highest number of drugs in advanced stages of development. The approved indications for drugs targeting MDM2 cover a wide range of cancers and hematologic neoplasms, indicating the potential effectiveness of these drugs in treating various diseases. Small molecule drugs, PROTACs, and synthetic peptides are the drug types progressing most rapidly, with intense competition observed in the biosimilar market. The United States, European Union, and several other countries/locations are actively developing drugs targeting MDM2, indicating a global effort in this field. Further analysis of the research and development institutions involved in biosimilars would provide valuable insights into the competitive landscape. Overall, the target MDM2 shows promising potential for future development in the pharmaceutical industry. MDM2 inhibitors entering Phase III clinical trials: IdasanutlinIdasanutlin is a small molecule drug that targets MDM2, a protein that plays a role in regulating the tumor suppressor protein p53. This drug is being developed for the treatment of various therapeutic areas including neoplasms, nervous system diseases, immune system diseases, cardiovascular diseases, hemic and lymphatic diseases, skin and musculoskeletal diseases, and urogenital diseases. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. In terms of active indications, idasanutlin is being investigated for the treatment of acute myeloid leukemia, acute lymphoblastic leukemia, neuroblastoma, solid tumors, prostatic cancer, breast cancer, diffuse large B-cell lymphoma, follicular lymphoma, multiple myeloma, polycythemia vera, and glioblastoma. These indications cover a wide range of cancers and highlight the potential versatility of idasanutlin in the field of oncology. The drug is being developed by F. Hoffmann-La Roche Ltd., a well-known pharmaceutical company. It has reached phase 3 of clinical development globally. In China, idasanutlin has reached phase 2, indicating progress in its development in this specific market. Idasanutlin has been designated as an orphan drug, which means it is intended to treat rare diseases or conditions. This designation provides certain incentives and benefits to the drug developer, such as market exclusivity and financial incentives, to encourage the development of treatments for rare diseases. In summary, idasanutlin is a small molecule drug that targets MDM2 and is being developed for the treatment of various therapeutic areas, particularly in the field of oncology. It has shown promise in multiple indications, including acute myeloid leukemia, solid tumors, and glioblastoma. With its orphan drug designation and advancement to phase 3 globally, idasanutlin represents a potential treatment option for patients with these diseases. MDM2 inhibitors entering Phase II clinical trials: AlrizomadlinAlrizomadlin is a small molecule drug that targets MDM2 and p53, making it a potential candidate for the treatment of various diseases. It falls under the therapeutic areas of neoplasms, congenital disorders, eye diseases, digestive system disorders, hemic and lymphatic diseases, immune system diseases, nervous system diseases, mouth and tooth diseases, skin and musculoskeletal diseases, and respiratory diseases. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. The drug has shown promise in the treatment of solid tumors, T-cell prolymphocytic leukemia, acute myeloid leukemia, salivary gland neoplasms, liposarcoma, cutaneous malignant melanoma, neurofibrosarcoma, non-small cell lung cancer, transitional cell carcinoma, uveal melanoma, hematologic neoplasms, myelodysplastic syndromes, lymphoma, chronic myelomonocytic leukemia, mixed phenotype acute leukemia, neuroblastoma, dystrophy, macular, stomach cancer, and retinoblastoma. Alrizomadlin is developed by Jiangsu Yasheng Pharmaceutical Development Co. Ltd., an originator organization in the pharmaceutical industry. Currently, the drug has reached Phase 2 of clinical development in both global and China trials. This indicates that it has progressed through initial safety testing and has shown potential efficacy in treating the targeted diseases. In terms of regulation, Alrizomadlin has been granted Fast Track designation, which expedites the development and review process by the regulatory authorities. Additionally, it has also received Orphan Drug status, indicating that it is intended to treat rare diseases. Furthermore, the drug has been recognized as a treatment for rare pediatric diseases. Based on the available information, Alrizomadlin shows promise as a potential therapeutic option for a wide range of diseases. Its small molecule nature and targeting of MDM2 and p53 make it a potentially versatile drug. However, further clinical trials and regulatory approvals are required to establish its safety and efficacy.

12 Apr 2021

·www.globenewswire.com

Global Acute Myeloid Leukemia (AML) Disease Analysis Report 2021: On Average, it Takes 10.8 Years from Phase I to Approval, Compared to 9.6 Years in the Overall Oncology Space

Dublin, April 12, 2021 (GLOBE NEWSWIRE) -- The "Disease Analysis: Acute Myeloid Leukemia (AML)" report has been added to ResearchAndMarkets.com's offering. AML is a type of heterogeneous hematological malignancy that originates from immature white blood cells (blasts) in the bone marrow, which may be derived from either a hematopoietic stem cell or a lineage-specific progenitor cell. "Acute" means that the leukemia may progress rapidly - AML generally spreads quickly to the bloodstream and can then spread to other parts of the body including the lymph nodes, spleen, central nervous system, and testicles.Latest Key TakeawaysThe publisher estimates that in 2018, there were 158,400 incident cases of acute myeloid leukemia (AML) worldwide and expects that number to increase to 169,000 incident cases by 2027. Approximately 60% of newly diagnosed patients are eligible for intensive chemotherapy, such as the 7+3 regimen of cytarabine and daunorubicin.Since 2017, there have been nine new drugs approved for AML in the US, dramatically changing the treatment landscape. Gone is the era where all front-line patients received either 7+3 chemotherapy or a hypomethylating agent (decitabine or azacitidine). Many of the new therapies target specific segments of AML or patients with specific mutations. As such, there is currently little competition between the new therapies, but that will change as therapies receive label expansions and new competitor therapies are approved.Two FLT3 inhibitors have been approved for FLT3-mutated AML: Rydapt for front-line patients eligible for intensive chemotherapy, and Xospata for relapsed/refractory patients. Rydapt may soon face competition in the front-line FLT3 setting as quizartinib, crenolanib, and Xospata are being evaluated in combination with standard chemotherapy and as single-agent maintenance therapies following either chemotherapy consolidation or hematopoietic stem cell transplant (HSCT). Approval in the lucrative maintenance setting would give these drugs a favorable long-term commercial outlook. Approximately 25-30% of AML patients have an FLT3 mutation.Tibsovo and Idhifa are approved in the US as oral, single-agent therapies for relapsed/refractory AML patients with IDH1 and IDH2 mutations, respectively. Tibsovo is also approved as a monotherapy for front-line patients over the age of 75 years. Both of these IDH inhibitors are now in Phase III trials in combination with standard induction (7+3) and consolidation chemotherapy and as maintenance therapy in front-line AML. Tibsovo is also being investigated in combination with azacitidine in a Phase III trial in front-line patients. Approval of Tibsovo and Idhifa in the EU will depend on these Phase III results. Tibsovo may face competition from FT-2102, an IDH1 inhibitor being evaluated in the relapsed/refractory setting in a pivotal single-arm Phase II trial. IDH1 mutations are present in 6-9% of AML, while IDH2 mutations are present in approximately 12% of cases.Mylotarg, an antibody-drug conjugate targeting CD33, is the only monoclonal antibody therapy approved for AML. Mylotarg combined with intensive chemotherapy is recommended for newly diagnosed patients with favorable cytogenetic risk (approximately 10% of patients eligible for intensive chemotherapy). Over 90% of AML patients are positive for CD33 expression.Vyxeos, a liposomal formulation of the 7+3 chemotherapy regimen, was approved in the US and EU for the treatment of newly diagnosed patients with secondary AML after showing an improvement in overall survival compared to the 7+3 regimen in patients ?60 years of age. Secondary AML accounts for approximately one third of new AML diagnoses, but most of these patients will be too frail for Vyxeos. Approximately 16% of patients eligible for intensive chemotherapy have secondary AML. Market access for Vyxeos is strengthened by positive recommendations from the US Centers for Medicare and Medicaid Services and from NICE in England and Wales.Venclexta combined with azacitidine is the new standard of care for newly diagnosed AML patients not suited for intensive chemotherapy (approximately 40% of newly diagnosed patients). A confirmatory Phase III trial evaluating Venclexta + azacitidine demonstrated a survival advantage (15 months versus 10 months) and supported regulatory submissions to European and Japanese authorities, with approvals expected in 2021. Venclexta is currently being evaluated in combination with novel agents in several trials, and a Phase III study (VIALE-M) is evaluating Venclexta combined with azacitidine as maintenance therapy for AML patients in first remission after conventional chemotherapy.Daurismo is the first and only Hedgehog pathway inhibitor approved for AML. Daurismo is approved in combination with low-dose cytarabine (LDAC) for newly diagnosed AML patients not suited for intensive chemotherapy, and will compete with Venclexta in this difficult-to-treat setting. However, in the US, hypomethylating agents are preferred over LDAC, so Venclexta may be preferred over Daurismo.Onureg, an oral formulation of azacitidine, increased overall survival and relapse-free survival in a Phase III trial and was approved in the US as a maintenance therapy following intensive chemotherapy for patients not suited for an HSCT. A European approval decision is expected in mid-2021. The maintenance setting would be a new setting for Vidaza (azacitidine) which is currently used in the EU (and off-label in the US) to treat newly diagnosed elderly AML patients.Rafael Pharmaceuticals is developing devimistat (CPI-613) as a first-in-class therapeutic targeting the altered mitochondrial metabolism present in many cancers, including AML. Devimistat's outlook will depend on the efficacy and safety results from a Phase III trial evaluating the drug in combination with high-dose cytarabine and mitoxantrone in relapsed/refractory AML patients. The first interim analysis is expected in Q2 2021.Chimerix's dociparstat sodium (DSTAT), a glycosaminoglycan analog of heparin designed to have reduced anticoagulant effects, targets the CXCR4 pathway which is involved in the homing and adhesion of AML cells to the bone marrow and is associated with resistance to systemic drugs. DSTAT is being developed in combination with intensive 7+3 chemotherapy for newly diagnosed AML, with the aim of improving the rate of durable response. A Phase III trial is enrolling patients with intermediate or unfavorable cytogenetic risk (74% of patients eligible for intensive chemotherapy).Otsuka's Inqovi is an oral formulation of decitabine that is being developed for patients with AML unsuited for intensive induction chemotherapy. In ASCERTAIN, a Phase III trial enrolling patients with MDS, Inqovi met the trial's primary endpoint of demonstrating pharmacokinetic equivalence to intravenous decitabine. ASCERTAIN has now been extended to include patients with AML in the EU, but a trial with efficacy endpoints will be needed to secure a US AML approval.Takeda's pevonedistat targets the NEDD8-activating enzyme in the ubiquitin-proteasome pathway, and is being developed in combination with azacitidine for a subpopulation of newly diagnosed, elderly AML patients categorized as low-blast count AML. Pevonedistat is also being evaluated in a randomized Phase II trial in combination with Venclexta and azacitidine in newly diagnosed AML patients unfit for intensive chemotherapy.Zeltherva is a therapeutic vaccine being developed as maintenance therapy for patients who have achieved hematologic complete remission, with or without thrombocytopenia, after second-line therapy and who are ineligible for allogeneic stem cell transplantation. Zeltherva's outlook in the specialized setting of CR2 will depend on results in REGAL, its Phase III trial. An interim analysis for safety and futility is expected in Q4 2021.Not including FLT3 and IDH inhibitors, there are five drugs in late-phase development for newly diagnosed AML patients. Dociparstat sodium and entospletinib are being developed in combination with intensive chemotherapy, while MBG453, pevonedistat, and Inqovi are being developed for elderly patients.Relapsed/refractory AML remains an area of unmet need, and new therapies are being developed. Not including FLT3 or IDH inhibitors, there are currently five late-stage therapies being evaluated for this setting (devimistat, DFP-10917, flotetuzumab, Iomab-B, and uproleselan).Key recent events include the approval of Onureg and presentation of numerical data from Venclexta's VIALE-A trial. There were Phase III failures for Helsinn's pracinostat combined with azacitidine in the newly diagnosed setting and for Roche's idasanutlin and Otsuka's guadecitabine in the relapsed/refractory setting. Other Phase III failures include trials evaluting Xospata combined with azacitidine and Daurismo combined with intensive chemotherapy in front-line AML, and an Idhifa monotherapy trial in the third- and fourth-line setting.Key upcoming catalysts for 2021 include topline results from Phase III trials for devimistat, Iomab-B, uproleselan, and Zeltherva, and a possible NDA submission for FT-2102.The overall likelihood of approval of a Phase I AML asset is 6.3%, and the average probability a drug advances from Phase III is 50%. AML drugs, on average, take 10.8 years from Phase I to approval, compared to 9.6 years in the overall oncology space. Companies Mentioned For more information about this report visit

AntibodyFirst in ClassVaccineADC

07 Apr 2021

·www.biospace.com

Rain Plans $100 Million IPO, Phase III Trial for Lead Precision Cancer Therapy

Newark, California-based cancer company Rain Therapeutics filed Friday for a $100 million IPO to advance its lead MDM2 inhibitor RAIN-32 into Phase III testing. The news comes months after the company closed a $63 million Series B and inlicensed RAIN-32 from Daiichi Sankyo. Rain licenses and develops precision cancer therapies. The new lead program, RAIN-32, previously completed Phase I testing in patients with solid tumors or lymphomas. The influx of cash will support a pivotal Phase III trial in liposarcoma, which Rain intends to launch this year, plus two more Phase II trials in solid tumors and intimal sarcoma, respectively. Preclinical data published by independent French researchers last year suggested MDM2 inhibitors had therapeutic potential for treating liposarcomas, where MDM2 amplification is common. MDM2 is an inhibitor of tumor-suppressive p53, a notoriously challenging drug target. Several companies are developing MDM2 inhibitors to act upstream of p53, with limited success, which Rain attributes to dose-limiting hematological toxicities. Last year, Roche ended development of its MDM2 inhibitor, idasanutlin, then in Phase II testing for patients with acute myeloid leukemia (AML). The most advanced anti-MDM2 therapy is APG-115, which Ascentage Pharma has in multiple Phase Ib/II trials for solid tumors and hematologic malignancies, plus a Phase II combination trial with checkpoint inhibitor Keytruda (pembrolizumab) for anti-PD-1 refractory or relapsed cancers. At least two other companies–Novartis and Aileron–also have MDM2 inhibitors in early clinical testing for several cancers. According to Rain, the safety and tolerability data from Daiichi Sankyo’s trial suggest RAIN-32 can be dosed longer than other MDM2-targeting programs in development. Rain also has a preclinical RAD52 inhibitor program, licensed from Drexel University in August 2020. RAD52 plays a role in DNA damage response and the company is exploring therapies for breast and ovarian cancers characterized by BRCA1/2 mutations. The company is aiming to select a lead clinical RAD52 inhibitor candidate in 2022. There are no known RAD52 inhibitors in clinical trials. As recently as last year, its previous lead candidate tarloxotinib, licensed from the University of Auckland, was in Phase II testing for patients with EGFR and ErbB Exon 20 insertion mutations in solid tumors. The company has not announced an end to the trial but tarloxotinib is not named in Rain’s Securities and Exchange Commission (SEC) forms or listed on the company’s website. Rain did not respond to a request for clarification in time for publication.

IPO

100 Deals associated with Idasanutlin

External Link

KEGG	Wiki	ATC	Drug Bank
D11219	-	-	DB12325

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Refractory acute myeloid leukemia	Phase 3	United States	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Australia	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Austria	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Belgium	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Canada	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Finland	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	France	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Germany	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Israel	Hoffmann-La Roche, Inc.	30 Dec 2015
Refractory acute myeloid leukemia	Phase 3	Italy	Hoffmann-La Roche, Inc.	30 Dec 2015

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02670044 (Pubmed) Manual	Phase 1	Acute Myeloid Leukemia	50	Venetoclax+idasanutlin	orhhamccvd(vojyhkiioc) = diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%) kcnhyltsen (rlxkqbzdua )	Positive	20 Oct 2022
NCT03850535 (CTgov)	Phase 1/2	Acute Myeloid Leukemia	24	idasanutlin+cytarabine+daunorubicin (Dose-Escalation Cohort 1)	sjzzygnweo = vomfhueeoo caryliyigw (suzlntgxww, jzjngzmmjs - ellhypagzm) View more	-	21 Jun 2022
				idasanutlin+cytarabine+daunorubicin (Dose Escalation Cohort 2)	sjzzygnweo = lgpzvekqqw caryliyigw (suzlntgxww, hvmmmfpzww - eizxmfdeuj) View more
NCT02545283 (MIRROS, Pubmed \| Blood Adv) Manual	Phase 3	Acute Myeloid Leukemia First line \| Second line \| Third line	447	Cytarabine+Idasanutlin	hhskcuoptt(puefwlfafd) = ixwbvpipzv jctngwlzam (rhpcrxkclg ) View more	Negative	12 Apr 2022
				Cytarabine+Placebo	hhskcuoptt(puefwlfafd) = snmznqawis jctngwlzam (rhpcrxkclg ) View more
NCT03287245 (Pubmed) Manual	Phase 2	Polycythemia Vera	16	Idasanutlin	wrwtwdzoug(holmvolsgg) = ewpyhqjqcp jryeyeocgy (rivbrqdset ) View more	Positive	22 Feb 2022
NCT02545283 (MIRROS, CTgov)	Phase 3	Relapsing acute myeloid leukemia \| Refractory acute myeloid leukemia	447	Placebo+Cytarabine (Placebo Plus Cytarabine)	hfbdfcpplf(aggkgoouet) = ofmoppjvko umebetebrs (bjxdmogrsh, cfbmmuqtok - fshxdznwax) View more	-	14 Sep 2021
				Idasanutlin+Cytarabine (Idasanutlin Plus Cytarabine)	hfbdfcpplf(aggkgoouet) = quoycibqbd umebetebrs (bjxdmogrsh, tioobqjcqf - wydzaqumff) View more
NCT03566485 (CTgov)	Phase 1/2	Metastatic breast cancer \| Estrogen receptor positive breast cancer \| Breast Cancer 3	12	Cobimetinib+Atezolizumab	ghyqoeijkx = xlmrkbdlrk qschvcwgvd (nunapiodzx, soglguucqg - fmtclyhtch) View more	-	11 Aug 2021
NCT01773408 (Pubmed \| Leuk Res) Manual	Phase 1	Acute Myeloid Leukemia	122	overall	xqxixxuczh(utnimjhbon) = The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. psiozmsmqg (tauzghoexi ) View more	Positive	01 Jan 2021
				cytarabine+Idasanutlin (TP53 wild-type pts)
NCT03135262 (ASH 12020 \| ASH 22020) Manual	Phase 1/2	Non-Hodgkin's lymphoma refractory	29	Idasanutlin+Venetoclax+Obinutuzumab	unhtwqxolo(ipydumlpxn) = 48.3% [neutropenia (10.3%)] wnslgqcmhk (jjmvkjwgab ) View more	Positive	05 Nov 2020
NCT02624986 (BH29812, EHA2020)	Phase 2	Follicular Lymphoma \| Diffuse Large B-Cell Lymphoma	25	Idasanutlin + Obinutuzumab	grccgbaovm(jnazqweupv) = All FL or DLBCL pts had ≥ 1 AE. 79.2% had ≥ 1 Grade 3/4 AEs, most commonly thrombocytopenia (75%), neutropenia (62.5%) and anaemia (37.5%). No Grade 5 AEs were reported. 37.5% of pts experienced SAEs, most commonly febrile neutropenia (8.3%) and diarrhoea (8.3%). Dose-limiting toxicity events were all Grade 3/4 thrombocytopenia. 37.5% of pts had an AE leading to withdrawal of study treatment, most commonly thrombocytopenia (25%) and neutropenia (8.3%). lreikrfjqc (ncaeiarkgu )	-	14 May 2020
				Idasanutlin + Rituximab
NCT02670044 (ASH 12019 \| ASH 22019) Manual	Phase 1	Refractory acute myeloid leukemia	49	Venetoclax+Idasanutlin	dpugbpmvjh(pfeebvxxjs) = febrile neutropenia (45%), neutropenia (27%), and thrombocytopenia (25%) xffdhhkpvu (mzzdpvxibu ) View more	Positive	13 Nov 2019

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