Navtemadlin for Endometrial Cancer
Palo Alto (17 mi)Age: 18+
Sex: Female
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: Kartos Therapeutics, Inc.
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests navtemadlin to see if it can prevent endometrial cancer from returning in patients who responded well to chemotherapy. The study will check the safety and effectiveness of different doses of the drug.
Is Navtemadlin a promising drug for endometrial cancer?The provided research articles do not mention Navtemadlin, so we cannot determine if it is a promising drug for endometrial cancer based on this information.347910
What data supports the idea that Navtemadlin for Endometrial Cancer is an effective drug?The available research does not provide any specific data or studies on the effectiveness of Navtemadlin for treating endometrial cancer. Instead, it discusses other treatments like paclitaxel plus carboplatin, enzalutamide, and progestin therapy with HDAC inhibitors. These treatments have shown varying levels of effectiveness in reducing tumor growth or improving patient outcomes. Without specific data on Navtemadlin, we cannot conclude its effectiveness for endometrial cancer based on the provided information.6891011
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you need to stop taking your current medications. However, it excludes those who have had prior immune therapy, cytokine therapy, or any investigational therapy within 28 days, which might suggest a washout period for certain treatments.
What safety data is available for Navtemadlin in endometrial cancer treatment?The provided research does not contain safety data for Navtemadlin (also known as AMG 232, KRT-232) in the treatment of endometrial cancer. The studies focus on other treatments such as amonafide, paclitaxel, amifostine, and ametantrone, none of which are related to Navtemadlin. Therefore, no relevant safety data for Navtemadlin is available in the provided research.125612
Eligibility Criteria
This trial is for patients with advanced or recurrent endometrial cancer who responded well to a specific chemo. They must have normal TP53 genes, good performance status (ECOG 0-1), and proper blood, liver, and kidney function. It's not for those with recent major bleeding, organ transplants, certain other cancers, recent experimental therapies or immune/cytokine therapy.Treatment Details
The study tests navtemadlin as a maintenance treatment after chemotherapy success in two parts: first to find the best dose comparing two levels of navtemadlin against observation; second to compare that dose's effectiveness and safety against a placebo.
7Treatment groups
Experimental Treatment
Active Control
Placebo Group
Group I: Part 2 Arm BExperimental Treatment1 Intervention
Navtemadlin administered orally at 240 mg once daily (QD) on Days 1-7 in a 28-day treatment cycles.
Group II: Part 2 Arm AExperimental Treatment1 Intervention
Navtemadlin administered orally at 180 mg once daily (QD) on Days 1-7 in a 28-day treatment cycles.
Group III: Part 1 Arm 2Experimental Treatment1 Intervention
Navtemadlin administered orally at 240 mg, once daily (QD) on Days 1-7 in a 28-day treatment cycles.
Group IV: Part 1 Arm 1Experimental Treatment1 Intervention
Navtemadlin administered orally at 180 mg, once daily (QD) on Days 1-7 in a 28-day treatment cycles.
Group V: Part 1 Arm 3Active Control1 Intervention
Observational control ("watch and wait") on a 28-day cycle.
Group VI: Part 2 Arm DPlacebo Group1 Intervention
Placebo administered orally at 240 mg once daily (QD) on Days 1-7 in a 28-day administration cycle.
Group VII: Part 2 Arm CPlacebo Group1 Intervention
Placebo administered orally at 180 mg once daily (QD) on Days 1-7 in a 28-day administration cycle.
Find a clinic near you
Research locations nearbySelect from list below to view details:
Good Samaritan Hospital Medical CenterWest Islip, NY
CHUM - University of Montreal Hospital CentreMontreal, Canada
St. JosephSavannah, GA
FirstHealth CarolinasPinehurst, NC
More Trial Locations
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Who is running the clinical trial?
Kartos Therapeutics, Inc.Lead Sponsor
European Network of Gynaecological Oncological Trial Groups (ENGOT)Collaborator
GOG FoundationCollaborator
References
Phase I investigation of ametantrone. [2013]Ametantrone is the third of a family of anthracene derivatives to undergo a phase I trial in man. Sixteen patients received 33 courses of drug as a single iv dose given every 3 weeks. Escalations proceeded from 120 to 180 mg/m2. Predictable and reversible leukopenia was the dose-limiting toxic effect. Four patients developed thrombocytopenia. Nonhematologic toxic effects included a marked cumulative blue discoloration of the skin seen in all patients receiving more than three courses of the drug. This cumulative cosmetic effect may also be dose-limiting. Other nonhematologic toxic effects included: blue urine (all patients), nausea (two), vomiting (one), a blue stool (one), and reversible elevations of either SGOT or alkaline phosphatase (two). No objective responses were seen in this study. A dose of 140-160 mg/m2 is recommended as the starting dose for phase II trials in patients who have received prior chemotherapy or radiotherapy.
Phase II trial of amonafide in patients with advanced metastatic or recurrent endometrial adenocarcinoma. A Southwest Oncology Group study. [2020]Amonafide, a benzisoquinoline-1,3-dione was administered to 38 patients with recurrent or metastatic, bidimensionally measurable endometrial cancer. There were 34 patients with no prior cytotoxic chemotherapy, performance status of 0-2, and normal bone marrow, renal, and hepatic function were eligible for response and toxicity evaluation. Amonafide, 300 mg/m2, was administered intravenously over 1 hour daily for 5 consecutive days. Courses were repeated every 21 days. The major grade 3 or 4 toxicities were hematologic with granulocytopenia in 18 patients (53%), thrombocytopenia in 6 patients (18%), and anemia in 8 patients (24%). Infectious complications occurred in 3 patients (9%). Other side effects included cardiac dysrhythmias, hypotension, pain and phlebitis at the site of injection, nausea, vomiting, and flu-like symptoms. The overall objective response rate was 6% (95% confidence interval of 1-20%); 2 patients had a complete response (6%), 9 patients had stable disease (26%) and 21 patients had progressive disease (62%). Two patients had insufficient follow-up for response determination and are assumed to be nonresponders. The median survival of the eligible patients was 8 months. With the toxicity observed and the low response rate, amonafide at this dose and schedule has no efficacy in the treatment of endometrial cancer.
Adrenomedullin promotes formation of xenografted endometrial tumors by stimulation of autocrine growth and angiogenesis. [2018]The angiogenic peptide adrenomedullin (ADM) has been implicated as a mediator of the increased risk of endometrial hyperplasia and cancer resulting from the use of tamoxifen for the treatment and prevention of breast cancer. ADM has been shown to be induced by tamoxifen in the endometrium and to be a growth factor for endometrial endothelial cells in vitro. We have now shown ADM to be strongly angiogenic in the mouse subcutaneous sponge angiogenesis assay. To examine the role of ADM in tumor growth, the ADM cDNA was transfected into endometrial carcinoma cells followed by xenografting into athymic mice. Two endometrial cancer cell lines were employed, those in which transfection and expression of ADM resulted in no effect on growthin vitro (Ishikawa cells) and those in which expressionof exogenous ADM stimulated in vitro growth (RL95.2 cells). A clear enhancement of tumor growth was seen with both cell lines but the effect was far greater with the RL95.2 cells. We conclude that ADM is pro-tumorigenic by stimulating either angiogenesis alone or by stimulating angiogenesis and carcinoma cell growth directly. The combined activities lead to a striking increase in tumor growth. These results provide the first direct evidence of tumorigenic activity of ADM and provide further support for ADMs involvement in tamoxifen induced endometrial neoplasia.
Treatment options for endometrial cancer: experience with topotecan. [2019]Although the prognosis for women with endometrial cancer confined to the uterus is relatively good, with a 5-year survival of approximately 90%, women with advanced or recurrent disease have a much poorer outcome. Systemic hormonal therapy with progestins improves survival in progesterone-receptor-positive tumors but chemotherapy is indicated as front-line therapy for most patients with this disease. Few single chemotherapy agents achieve response rates greater than 20%. The combination of doxorubicin and cisplatin is the first-line treatment of choice but the response and survival rates are still low compared to ovarian cancer treatments and more active regimens are needed. Treatment options for second-line chemotherapy are even more limited because of low response rates and toxicity issues related to prior radiation therapy. The topoisomerase I inhibitor, topotecan, is being investigated for the treatment of endometrial cancer. In previously treated patients, single-agent topotecan achieved a response in 10% of patients and disease stabilized in 55% of patients. The combination of topotecan and cisplatin is being studied in chemotherapy-naive elderly patients. Topotecan is also active in uterine papillary serous carcinoma, an aggressive form of the disease that generally does not respond to chemotherapy.
A potential synergistic anticancer effect of paclitaxel and amifostine on endometrial cancer. [2015]Although paclitaxel is one of the most effective chemotherapeutic agents, its usefulness is still limited in advanced and recurrent endometrial cancer. Amifostine protection of normal tissues against the side effects of chemotherapeutic agents has been clinically proven in cancer patients; however, its application in endometrial cancer has not been fully evaluated. We have investigated the use of paclitaxel and amifostine in controlling the growth of poorly differentiated endometrial cancer cells, Hec50co, in vitro and in vivo. Our studies show that amifostine had direct anticancer effects on endometrial cancer cells in vitro by arresting the cell cycle at the G1 phase and inducing apoptosis. Amifostine also inhibited s.c. tumor growth in athymic mice. Paclitaxel IC50 value was reduced from 14 to 2 nmol/L with pretreatment of a single dose of 178 micromol/L of amifostine for 72 hours. Amifostine also synergized with paclitaxel in the arrest of the cell cycle at the G2-M phase and in the induction of apoptosis. This two-drug regimen inhibited s.c. tumor growth as well as improved mouse survival significantly more than paclitaxel alone. Amifostine also significantly improved paclitaxel-induced cytotoxic effects on peripheral blood profiles. Our studies show that amifostine has direct anticancer effects on endometrial cancer. Our data have also shown a potential anticancer synergy between amifostine and paclitaxel in vitro and in vivo, whereas amifostine maintained a protective role in peripheral blood profiles. The dual specificity of amifostine action should be further investigated.
Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. [2015]The goal of this study was to evaluate the efficacy and toxicity of paclitaxel plus carboplatin in the treatment of primarily advanced or recurrent endometrial carcinoma.
A phase II trial of thalidomide in patients with refractory endometrial cancer and correlation with angiogenesis biomarkers: a Gynecologic Oncology Group study. [2018]A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of thalidomide in persistent or recurrent endometrial cancer refractory to cytotoxic chemotherapy and to correlate angiogenesis biomarker expression with clinical outcome.
Immunotherapy in endometrial cancer - an evolving therapeutic paradigm. [2023]Endometrial cancer is the only gynecologic malignancy with a rising incidence and mortality. While cure is routinely achieved with surgery alone or in combination with adjuvant pelvic radiotherapy when disease is confined to the uterus, patients with metastatic or recurrent disease exhibit limited response rates to cytotoxic chemotherapy, targeted agents, or hormonal therapy. Given the unmet clinical need in this patient population, exploration of novel therapeutic approaches is warranted, and attention is turning to immunomodulation of the tumor microenvironment. Existing evidence suggests that endometrial cancer is sufficiently immunogenic to be a reasonable candidate for active and/or passive immunotherapy. In this review, we critically examine what is known about the microenvironment in endometrial cancer and what has been learned from preliminary immunotherapy trials that enrolled endometrial cancer patients, encouraging further attempts at immunomodulation in the treatment of aggressive forms of this disease.
Dose dense carboplatin paclitaxel improves progression free survival in patients with endometrial cancer. [2022]Pilot study to assess the value of weekly paclitaxel plus carboplatin every 3weeks (dose dense regimen, DD) compared to the standard 3-weekly protocol in the adjuvant setting for endometrial cancer.
Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma. [2021]Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.
Enhancing progestin therapy via HDAC inhibitors in endometrial cancer. [2023]Uterine endometrial cancer (EC) incidence and deaths are on the rise. Hormone therapy, a traditional treatment regimen for this disease, uses progesterone and its synthetic analogue, progestin, to induce cell differentiation, apoptosis, and inhibition of invasion. This therapy is highly effective for progesterone receptor (PR) positive tumors in the short term. However, responsiveness decreases over time due to loss of PR expression; acquired resistance leads to treatment failure and poor prognosis. Primary resistance occurs in advanced, PR-negative tumors. Regardless, progestin therapy can be effective if the PR downregulation mechanism is reversed and if functional PR expression is restored. Using histone deacetylase inhibitors (HDACi), we inhibited cell proliferation in three EC cell lines and restored functional PR expression at the mRNA and protein levels. Two HDACi were tested using an endometrial xenograft tumor model: entinostat, an oral drug, and romidepsin, an IV drug. In vitro and in vivo studies support that entinostat decreased EC tumor growth, induced differentiation, and increased expression of the PR-targeted gene, PAEP. These findings supported the approval of a new NIH NCTN clinical trial, NRG-GY011, which concluded that dual treatment of MPA and entinostat, decreased expression of the proliferation marker, Ki67, but did not increase PR expression relative to single treatment with MPA in this short-term study. Therefore, a more potent HDACi, romidepsin, was investigated. Romidepsin treatment inhibited tumor growth and enhanced progestin treatment efficacy. More importantly, PR, PAEP, and KIAA1324 expressions were upregulated. Using a chromatin immunoprecipitation assay, we verified that HDACi can reverse PR downregulation mechanisms in mice models. Other potential drug efficacy markers, such as CD52, DLK1, GALNT9, and GNG2, were identified by transcriptome analysis and verified by q-PCR. Many of the upregulated drug efficacy markers predict favorable patient outcomes, while downregulated genes predict worse survival. Here, our current data suggests that romidepsin is a more potent HDACi that has the potential to achieve more robust upregulation of PR expression and may be a more promising candidate for future clinical trials.
The Evolving Landscape of Immunotherapy in Uterine Cancer: A Comprehensive Review. [2023]Endometrial cancer affects the uterus and is becoming increasingly common and deadly. Although surgery and adjuvant pelvic radiotherapy can often cure the disease when it is contained in the uterus, patients with metastatic or recurrent disease have limited response rates to chemotherapy, targeted agents, and hormonal therapy. To address this unmet clinical need, innovative treatment strategies are needed, and a growing focus on the immunomodulation of the tumor microenvironment has arisen. Current data suggest that active and/or passive immunotherapy may be promising for the treatment of endometrial cancer.