A Phase 2/3 Study of Navtemadlin as Maintenance Therapy in Subjects with TP53WT Advanced or Recurrent Endometrial Cancer Who Responded to Chemotherapy
- Trial ID
- 2022-502196-31-00
- Protocol
- KRT-232-118
- Sponsor
- Kartos Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2/3 study is to determine the **navtemadlin** Phase 3 dose in Part 1 and to compare the progression-free survival (PFS) by independent review committee (IRC) between **navtemadlin** and placebo in Part 2. This is clinically relevant as it aims to establish an effective maintenance therapy dose for patients with TP53WT advanced or recurrent endometrial cancer, potentially improving their PFS outcomes.
Secondary objectives include:
- Part 1: Evaluating the treatment effect of **navtemadlin** on PFS by IRC and investigator assessment.
- Part 2: Evaluating the treatment effect of **navtemadlin** on PFS by investigator assessment and on the time to first subsequent treatment (TFST).
- Part 1 and Part 2: Evaluating the treatment effect of **navtemadlin** on overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Additionally, determining the pharmacokinetic (PK) profile of **navtemadlin** and evaluating its safety and tolerability.
Participants
The clinical trial involves a total of **166 participants** diagnosed with **advanced or recurrent endometrial cancer**. The study population is exclusively female, aged **18 years and older**, and includes individuals who are able to provide informed consent. Participants were selected based on a confirmed histological or cytological diagnosis of endometrial cancer, with specific subtypes documented as TP53WT. The trial includes subjects who have experienced a first relapse after completing a single line of up to six cycles of taxane-platinum combination chemotherapy, achieving either a complete or partial response. Participants must have an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate hematologic, hepatic, and renal functions are required, with specific laboratory criteria outlined for eligibility. Lifestyle considerations include the requirement for female subjects of childbearing potential and their male partners to use highly effective contraception during the study and for a specified period after the last dose of the study drug. The trial does not include male participants, and the population is considered vulnerable. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **navtemadlin** as a maintenance therapy in subjects with advanced or recurrent endometrial cancer. This is a Phase 2/3, randomized, double-blind, placebo-controlled study. The trial is divided into two parts: Part 1 aims to determine the Phase 3 dose of navtemadlin, while Part 2 compares progression-free survival (PFS) between navtemadlin and placebo. The estimated duration of the trial is from August 16, 2023, to August 17, 2028.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis, and previous treatment response. Following successful screening, participants will be randomized to receive either navtemadlin or a placebo. Study visits will include regular follow-up assessments to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of their health status and study outcomes.
The expected length of participant involvement is up to 24 months, depending on individual response and progression. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants are required to adhere to the study protocol, including the use of effective contraception methods if applicable, to ensure the integrity of the trial data.
Treatment
The clinical trial involves the administration of **Navtemadlin**, an experimental medication, in two formulations: Navtemadlin 25-30 and Navtemadlin 25-60. Both formulations are provided in tablet form and are administered orally. The active substance, Navtemadlin, is a chemical compound classified as an MDM2 inhibitor. The maximum daily dose for Navtemadlin is 240 mg, with a total maximum dose of 40,320 mg over a treatment period of 24 weeks. Participant compliance with the dosing schedule is monitored throughout the trial.
**Loperamide** is used as an auxiliary treatment in the study. It is available in two forms: an orodispersible tablet and a film-coated tablet, both administered orally. The active substance, Loperamide, is a chemical compound used as an antipropulsive agent. The maximum daily dose is 16 mg, with a total maximum dose of 56 mg over a 24-week period. The film-coated tablet form is over-encapsulated for Part 2 of the study.
**Ondansetron** is another auxiliary treatment included in the trial. It is provided in two forms: a film-coated tablet and a standard tablet, both administered orally. Ondansetron is a chemical compound classified as a 5-HT3 antagonist. The maximum daily dose is 16 mg, with a total maximum dose of 2,688 mg over a 24-week period. The film-coated tablet form is over-encapsulated for Part 2 of the study.
Placebos are used as comparator treatments in the study. These include a placebo to match Navtemadlin, provided as a film-coated tablet, a placebo to match Loperamide, provided as a capsule, and a placebo to match Ondansetron, also provided as a capsule. These placebos are designed to match the appearance and administration route of their respective active treatments to maintain blinding in the trial.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Part 2 of the study is progression-free survival (PFS), defined as the time from randomization to disease progression as determined by an independent review committee (IRC) or death, whichever occurs first. This will be compared between the treatment group receiving **Navtemadlin** and the placebo group. In Part 1, the primary endpoint involves determining the Phase 3 dose of **Navtemadlin** based on safety data.
Secondary endpoints include PFS as assessed by the investigator, time to first subsequent therapy (TFST), overall survival (OS), and response rates per RECIST 1.1 criteria. Additionally, pharmacokinetic parameters of **Navtemadlin** and its metabolite will be evaluated, including maximum observed concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC). The incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs) will also be monitored, along with changes in laboratory values, electrocardiograms (ECGs), and vital signs.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Female ≥18 years of age and able to provide informed consent.
- Histologically or cytologically confirmed diagnosis of endometrial cancer (including endometroid adenocarcinoma, serous carcinoma, papillary serous carcinoma, adeno-squamous carcinoma, clear cell carcinoma, mixed carcinoma, undifferentiated carcinoma, carcinosarcoma, and carcinoma not otherwise specified) documented as TP53WT. In Part 2, TP53WT to be determined by central testing.
- Subjects with advanced or recurrent disease (ie, first relapse) must have completed a single line of up to 6 cycles of taxane-platinum combination chemotherapy (not including adjuvant or neoadjuvant therapy) and achieved a CR or PR per RECIST V1.1. • Primary Stage IV disease, defined as: − had a primary or later debulking surgery during first-line platinum therapy with R0 resection (R0 resection indicates a macroscopic complete resection of all visible tumor), OR − had a primary or later debulking surgery during first-line taxane-platinum therapy with R1 resection (R1 resection indicates incomplete removal of all macroscopic disease), OR − had no surgery. • Subjects at first relapse (ie, relapse after primary therapy including surgery and/or chemotherapy with or without immunotherapy for Stage I-IV disease), defined as: − had Stage I-III disease at diagnosis and received adjuvant chemotherapy with or without immunotherapy at initial diagnosis and relapsed later, OR − had Stage I-III disease at diagnosis and did not receive adjuvant chemotherapy with or without immunotherapy at initial diagnosis and relapsed later, OR − had Stage IV disease at diagnosis and initially received immunotherapy or endocrine therapy/with or without surgery and relapsed later. Note: Subjects that required dose interruption of their current chemotherapy may be considered eligible if they meet the other criteria above and achieve CR or PR per RECIST V1.1.
- Subjects must be able to initiate study treatment within 6 weeks after completion of their final dose of chemotherapy.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Adequate hematologic function within 14 days prior to first dose of study treatment and independent of growth factor support for at least 7 days with the exception of pegylated granulocyte-colony stimulating factor (G-CSF) which require at least 14 days, defined as: a. ANC ≥ 1.0 x 10^9/L b. Platelet count ≥ 75 x 10^9/L
- Adequate hepatic function within 14 days prior to the first dose of study treatment defined as: a. Total serum bilirubin within normal limits. If total bilirubin is > upper limit of normal (ULN), then subjects are eligible if the direct bilirubin is ≤ 2.0 x ULN b. Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN. For subjects with liver involvement: AST and ALT ≤ 5 x ULN.
- Adequate renal function within 14 days prior to first dose of study treatment defined as an estimated creatinine clearance ≥30 mL/min by Cockcroft Gault
- Female subjects of childbearing potential and their male partners must both use a highly effective contraception method during the study (Appendix 2 of the protocol). In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 month and 1 week. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming post-menopausal) unless permanently sterile (Appendix 2 of the protocol).
Exclusion Criteria
- Has any sarcomas or small-cell carcinomas with neuroendocrine differentiation.
- Received immune therapy, cytokine therapy, or any investigational therapy within 28 days prior to the first dose of study treatment.
- Participation in another interventional clinical study within 28 days prior to the first dose of study treatment (participation in observational studies is permitted)
- Uncontrolled clinically significant cardiac disease (New York Heart Class III or IV), symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia or history of myocardial infarction within 3 months prior to the first dose of study treatment
- Indwelling surgical drains (eg, peritoneal, central nervous system [CNS], or pleural)
- Active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
- Grade 2 or higher QTc prolongation >480 msec per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
- History of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment
- History of another malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
- History of major organ transplant
- Known active hepatitis B or C infection
- Known infection with human immunodeficiency virus
- Clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection. Intravenous (IV) antibiotics within 2 weeks prior to first dose of study treatment
- Known hypersensitivity to or contraindications to the study drug or any of its excipients, or to required prophylaxes
- Major surgery or planned major surgery within 28 days prior to first dose of study treatment
- History of difficult swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study treatment
- Women who are pregnant or breastfeeding
- Medical condition, serious intercurrent illness, psychiatric condition, or other circumstance (ie, committed to an institution by judicial or administrative authority) that, in the investigator's judgment, could jeopardize the subject's safety, or that could interfere with study objectives
- Subjects with indwelling surgical drains (e.g., peritoneal, CNS, or pleural)
- Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 16 Aug 2023 | 6 |
 Czechia | Not Recruiting | 16 Aug 2023 | 8 |
 Denmark | Not Recruiting | 16 Aug 2023 | 6 |
 Estonia | Not Recruiting | 16 Aug 2023 | 2 |
 Finland | Not Recruiting | 16 Aug 2023 | 6 |
 France | Not Recruiting | 16 Aug 2023 | 24 |
 Hungary | Not Recruiting | 16 Aug 2023 | 2 |
 Italy | Not Recruiting | 16 Aug 2023 | 20 |
 Lithuania | Not Recruiting | 16 Aug 2023 | 6 |
 Norway | Not Recruiting | 16 Aug 2023 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
LOPERAMIDE | Other | — | ORAL | 16 | 24 | SUB08572MIG |
Placebo to match ondansetron, capsule | Placebo | N/A | — | — | — | N/A |
Navtemadlin 25-30 | Test | TABLET | ORAL | 240 | 24 | PRD10314828 |
ONDANSETRON | Other | — | ORAL | 16 | 24 | SUB09445MIG |
Placebo to match navtemadlin, film coated tablet | Placebo | N/A | — | — | — | N/A |
ONDANSETRON | Other | — | ORAL | 16 | 24 | SUB09445MIG |
Placebo to match loperamide, capsule | Placebo | N/A | — | — | — | N/A |
LOPERAMIDE HYDROCHLORIDE | Other | — | ORAL | 16 | 24 | SUB02969MIG |
Navtemadlin 25-60 | Test | TABLET | ORAL | 240 | 24 | PRD10314829 |
- | Other | PHF00082MIG | ORAL | 16 | 24 | A04AA |