Phase 2/3 Study of Navtemadlin as Maintenance Therapy in TP53WT Advanced or Recurrent Endometrial Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Kartos Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Aug 2023 → 29 Aug 2024

Decision date (initial)

2023-07-25

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Kartos Therapeutics, Inc.

External identifiers

EU CT number

2022-502196-31-00

WHO UTN

U1111-1288-5667

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Safety, Pharmacodynamic, Efficacy, Dose response

Part 1
To determine the navtemadlin Phase 3 dose

Part 2
To compare the progression-free survival (PFS) by independent review committee (IRC) between navtemadlin and placebo

Secondary objectives 3

1. Part 1 To evaluate the treatment effect of navtemadlin on PFS by IRC and investigator assessment
2. Part 2 • To evaluate the treatment effect of navtemadlin on PFS by investigator assessment • To evaluate the treatment effect of navtemadlin on the time to first subsequent treatment (TFST)
3. Part 1 and Part 2 • To evaluate the treatment effect of navtemadlin on overall survival (OS) • To evaluate the treatment effect of navtemadlin on the objective response rate (ORR) • To evaluate the treatment effect of navtemadlin on the disease control rate (DCR) • To determine the pharmacokinetic (PK) profile of navtemadlin • To evaluate the safety and tolerability of navtemadlin

Conditions and MedDRA coding

Advanced or Recurrent Endometrial Cancer

Study design 8 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Female ≥18 years of age and able to provide informed consent.
2. 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.
3. 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.
4. Subjects must be able to initiate study treatment within 6 weeks after completion of their final dose of chemotherapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
6. 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
7. 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.
8. 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
9. 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 20

1. Has any sarcomas or small-cell carcinomas with neuroendocrine differentiation.
2. Received immune therapy, cytokine therapy, or any investigational therapy within 28 days prior to the first dose of study treatment.
3. Participation in another interventional clinical study within 28 days prior to the first dose of study treatment (participation in observational studies is permitted)
4. 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
5. Indwelling surgical drains (eg, peritoneal, central nervous system [CNS], or pleural)
6. Active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment
7. Grade 2 or higher QTc prolongation >480 msec per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
8. History of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment
9. 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
10. History of major organ transplant
11. Known active hepatitis B or C infection
12. Known infection with human immunodeficiency virus
13. Clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection. Intravenous (IV) antibiotics within 2 weeks prior to first dose of study treatment
14. Known hypersensitivity to or contraindications to the study drug or any of its excipients, or to required prophylaxes
15. Major surgery or planned major surgery within 28 days prior to first dose of study treatment
16. 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
17. Women who are pregnant or breastfeeding
18. 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
19. Subjects with indwelling surgical drains (e.g., peritoneal, CNS, or pleural)
20. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part 1: Safety review committee (SRC) will determine the navtemadlin Phase 3 dose for Part 2 based on safety data from Part 1. Part 2: PFS defined as the time from randomization to disease progression by IRC or death, whichever occurs first

Secondary endpoints 7

1. Part 1: PFS defined as the time from randomization to disease progression by IRC/investigator assessment or death, whichever occurs first
2. Part 2: - PFS defined as the time from randomization to disease progression by investigator assessment or death, whichever occurs first. - TFST defined as the time from randomization to initiation of first subsequent anti-cancer therapy or death, whichever occurs first.
3. Part 1&2: OS defined as the time from randomization to death of any cause
4. Part 1&2: IRC/investigator assessed response per RECIST 1.1 (Appendix 4 of the protocol)
5. Part 1&2: Best response of complete response (CR), partial response (PR) or stable disease (SD) by IRC/investigator assessment among subjects with PR as best response from prior chemotherapy
6. Part 1&2: Navtemadlin and acyl glucuronide metabolite (M1) PK parameters, including but not limited to: • Maximum observed concentration (Cmax) • Time to maximum plasma concentration (Tmax) • Area under the plasma concentration-time curve (AUC)
7. Part 1&2: • Incidence, nature and severity of adverse events (AEs) and serious adverse events (SAEs) • Changes in laboratory values, electrocardiograms (ECGs) and vital signs

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 3

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Kartos Therapeutics Inc.

Sponsor organisation

Kartos Therapeutics Inc.

Address

275 Shoreline Drive Suite 300

City

Redwood City

Postcode

94065-1490

Country

United States

Scientific contact point

Organisation

Kartos Therapeutics Inc.

Contact name

Clinical Operations Lead

Public contact point

Organisation

Kartos Therapeutics Inc.

Contact name

Clinical Operations Lead

Third parties 13

Locations

15 EU/EEA countries · 91 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

17 submissions — initial application plus substantial / non-substantial modifications