AZD3470 for Advanced Solid Cancers (PRIMROSE Trial)
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: AstraZeneca
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called AZD3470 in patients with advanced cancers that have a specific genetic issue. The goal is to see if the drug is safe, well-tolerated, and effective in stopping or slowing down cancer growth. AZD3470 is being tested for its potential to treat cancers with this genetic issue, which has been linked to a dependency on a specific protein, making it a target for new cancer therapies.
Do I need to stop my current medications to join the trial?The trial protocol does not specify if you need to stop your current medications. However, unresolved toxicities from prior anti-cancer therapy are an exclusion criterion, so discuss your current medications with the trial team.
Is the drug AZD3470 a promising treatment for advanced solid cancers?The information provided does not include any specific details about AZD3470, so we cannot determine if it is a promising treatment for advanced solid cancers based on the given research articles.126912
What safety data is available for AZD3470 in treating advanced solid cancers?The provided research does not contain any safety data specifically for AZD3470. The studies mentioned focus on other drugs such as AZD5153, AZD1775, AZD4635, and AZD4547, each with their own safety profiles and clinical trial results. Therefore, no safety data for AZD3470 is available in the given research.7891012
What data supports the idea that AZD3470 for Advanced Solid Cancers is an effective treatment?The available research does not provide any specific data or studies on AZD3470 for Advanced Solid Cancers. The articles focus on other treatments and conditions, such as prostate cancer and breast cancer, but do not mention AZD3470. Therefore, there is no data available in the provided information to support the effectiveness of AZD3470 for Advanced Solid Cancers.3451113
Eligibility Criteria
This trial is for adults with advanced or metastatic solid tumors that lack MTAP, a specific gene. Participants must have tried standard treatments without success and should be in fairly good health (able to perform daily activities with ease or some limitation). They need at least one tumor that can be measured by medical scans and should expect to live at least 12 more weeks.Inclusion Criteria
I am at least 18 years old or the legal age of consent where the study is conducted.
My cancer has not responded to or I cannot tolerate the standard treatment, and I have had at least one treatment for it when it came back or spread.
My tumor lacks MTAP due to gene deletion or no MTAP protein expression.
I am fully active or can carry out light work.
Treatment Details
The study tests AZD3470, a new drug targeting PRMT5 enzymes in patients whose tumors don't have the MTAP gene. It's an early-phase trial assessing how safe the drug is, how well it's tolerated, its pharmacokinetics (how it moves through the body), effects on the body, and initial signs of effectiveness.
1Treatment groups
Experimental Treatment
Group I: AZD3470 MonotherapyExperimental Treatment1 Intervention
Part A dose escalation and back-fill cohorts and Part B dose optimization and expansion cohorts of varying doses of AZD3470
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Research locations nearbySelect from list below to view details:
Research SiteBaltimore, MD
Research SiteSan Francisco, CA
Research SiteProvidence, RI
Research SitePittsburgh, PA
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Who is running the clinical trial?
AstraZenecaLead Sponsor
References
Regulation of tumor signaling pathways by AZD3409 in vitro. [2007]The antineoplastic activity of AZD3409 was evaluated in relation to paclitaxel in human breast (MDA-MB-231, BT-474) and ovarian (A2780, A2780cp) cancer cell lines. Biomarkers of apoptosis, protein prenylation, survival, angiogenesis and cellular growth were determined.
Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. [2015]AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non-small-cell lung cancer.
A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen. [2018]To determine if concomitant administration of docetaxel plus zosuquidar.3HC1 can prolong progression-free survival in patients with metastatic breast cancer.
AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo. [2021]Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
Optimisation of an immunohistochemistry method for the determination of androgen receptor expression levels in circulating tumour cells. [2021]AZD3514 inhibits and down regulates the androgen receptor (AR) and has undergone clinical trials in prostate cancer. To provide proof-of-mechanism (POM) in patients, an immunohistochemistry (IHC) method for determination of AR in circulating tumour cells (CTC) was developed and validated.
Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. [2019]Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies.
A Phase I Clinical Trial of AZD1775 in Combination with Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck Squamous Cell Carcinoma. [2021]Purpose: The WEE1 tyrosine kinase regulates G2-M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel.Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data.Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in γH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders.Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740-8. ©2018 AACR.
Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients. [2020]Purpose: AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood-brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma.Patients and Methods: Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm. Sparse pharmacokinetic blood samples were collected, and contrast-enhancing tumor samples were collected intraoperatively. AZD1775 total and unbound concentrations were determined by a validated LC/MS-MS method. Population pharmacokinetic analysis was performed to characterize AZD1775 plasma pharmacokinetic profiles. Pharmacodynamic endpoints were compared to matched archival tissue.Results: The AZD1775 plasma concentration-time profile following a single oral dose in patients with glioblastoma was well-described by a one-compartment model. Glomerular filtration rate was identified as a significant covariate on AZD1775 apparent clearance. AZD1775 showed good brain tumor penetration, with a median unbound tumor-to-plasma concentration ratio of 3.2, and achieved potential pharmacologically active tumor concentrations. Wee1 pathway suppression was inferred by abrogation of G2 arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study.Conclusions: In contrast to recent preclinical data, our phase 0 study of AZD 1775 in recurrent glioblastoma indicates good human brain tumor penetration, provides the first evidence of clinical biological activity in human glioblastoma, and confirms the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma. Clin Cancer Res; 24(16); 3820-8. ©2018 AACRSee related commentary by Vogelbaum, p. 3790.
SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients With Fibroblast Growth Factor Pathway-Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy). [2022]S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting.
Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations. [2023]Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635.
The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES. [2023]Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment.
First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma. [2023]AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.
Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial. [2023]Label="PURPOSE" NlmCategory="OBJECTIVE">Phase III PROfound trial (ClinicalTrials.gov identifier: NCT02987543) met its primary and key secondary objectives, demonstrating significantly longer radiographic progression-free survival (rPFS) and overall survival (OS) with olaparib monotherapy versus abiraterone or enzalutamide (control) in patients with metastatic castration-resistant prostate cancer (mCRPC) with alterations in BRCA1, BRCA2 (BRCA), and/or ATM (cohort A) whose disease had progressed on prior next-generation hormonal agent (NHA). We report exploratory post hoc analysis of the subgroup of patients with mCRPC with BRCA alterations in PROfound.