Evaluating dostarlimab as a non-surgical treatment for early-stage endometrial cancer

A Phase 2b, Open-label, Single Arm, Multicentre, Pilot Study of the Efficacy, Safety and Tolerability of Dostarlimab in Women With Early-stage MMR Deficient Endometrioid Endometrial Adenocarcinoma.

This study is testing if a new immunotherapy drug called dostarlimab can be a safe and effective non-surgical treatment for women with early-stage endometrial cancer who want to keep their fertility or can't have surgery.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 18 Years and up
• Sex: Female
• Sponsor: Queensland Centre for Gynaecological Cancer (Government)
• Drugs / interventions: dostarlimab, immunotherapy, prednisone
• Locations: 3 sites (Sydney, New South Wales and 2 other locations)
• Trial ID: NCT06278857 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to assess the efficacy and safety of dostarlimab, an immunotherapy drug, as a potential alternative to surgery for women with early-stage endometrial cancer characterized by Mismatch Repair deficiency. Participants will receive seven doses of dostarlimab over a 12-month period, with treatment cycles designed to enhance the immune response against cancer. The study focuses on women who wish to preserve their fertility or are not suitable candidates for surgical intervention, thereby expanding treatment options for this patient population.

Who should consider this trial

Good fit: Ideal candidates for this study are women aged 18 and older with Stage 1, MMR deficient endometrioid endometrial adenocarcinoma who wish to preserve their uterus or are unsuitable for surgery.

Not a fit: Patients with advanced endometrial cancer or those who do not have MMR deficiency may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a less invasive treatment option for women with early-stage endometrial cancer, potentially preserving fertility and reducing surgical risks.

How similar studies have performed: While dostarlimab has been approved for advanced cases, this study represents a novel approach in evaluating its effectiveness for early-stage endometrial cancer.

Eligibility criteria

Inclusion Criteria:

1. Female participant is at least 18 years of age (at the time of informed consent).
2. Participant has:

   i. histologically or cytologically proven Stage 1, FIGO grade 1 or 2, MMR deficient (Absence of at least one MMR protein (MLH1, PMS2, MSH2, MSH6) by immunohistochemistry.) endometrioid endometrial adenocarcinoma, and

   ii. wish to preserve the uterus or are not a suitable candidate for hysterectomy.
3. Participant has an ECOG performance status of ≤ 2
4. Participant demonstrates no evidence of extrauterine disease assessed from all available clinical evidence (physical examination findings) and medical imaging including standard of care diagnostic CT, MRI, ultrasound, or X-ray and screening gadolinium contrast pelvic MRI
5. Participants must have adequate organ and bone marrow function defined as:

   i. absolute neutrophil count 1.5 x 109/L ii. platelets 100 x 109/L iii. haemoglobin ≥9 g/dL

   Adequate liver function:

   iv. total bilirubin \< 1.5x institutional upper limit normal (ULN) v. AST/ALT \< 2. 5 - 3x ULN

   Adequate renal function as defined by:

   vi. Creatinine \< 1.5x institutional upper limits OR creatinine clearance \> 30 ml/min

   Adequate coagulation profile:

   vii. INR or PT ≤ 1.5 x ULN unless the participant is receiving anticoagulant therapy as long as INR or PTT is within the therapeutic range of intended use of anticoagulants viii. aPTT ≤ 1.5 x ULN unless the patient is receiving anticoagulant therapy as long as INR or PTT is within the therapeutic range of intended use of anticoagulant
6. A potential participant with a clinical abnormality or laboratory parameters outside the normal reference range for the population being studied may be rescreened once, at the Investigator's discretion, and may be included only if the Investigator considers that the finding is unlikely to introduce additional risk factors to the participant and will not interfere with the study procedures.
7. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at enrolment prior to each treatment cycle and use a highly effective contraceptive method including; oral contraceptive pills \[OCPs\], or an intrauterine hormone device \[IUD\]) from screening until at least 4 months following the last dose of dostarlimab. Females who are abstinent from heterosexual intercourse as part of their usual lifestyle do not need to use contraception.
8. Post-menopausal females. Post-menopausal status will be confirmed through testing of follicle-stimulating hormone (FSH) levels (≥ 40 IU/mL) at screening for amenorrhoeic (≥ 12 months) female participants.
9. Participants with confirmed Type I or Type II diabetes mellitus must be well controlled by medication and/or diet and have glycated haemoglobin (HBAc1) \< 8.5% at screening and be willing to monitor blood glucose levels at home during study participation.
10. Participants must have normal blood pressure (BP) or adequately treated and controlled hypertension.
11. Participant is able to provide written informed consent and are willing to participate for the duration of the study and to follow study procedures.

Exclusion Criteria:

1. Participant has a histological (cell) type other than endometrioid adenocarcinoma (sarcomas or high-risk endometrial e.g., papillary serous, clear cell).
2. Participant is pregnant, breastfeeding, or planning to become pregnant during the trial period.
3. Participant has had an allogeneic tissue/solid organ transplant.
4. Participants with uncontrolled hypertension, history of hypertension crisis, history of hypertensive encephalopathy, QTc\>450 at baseline, other severe cardiovascular diseases including cerebrovascular accident (CVA), transient ischemic attack (TIA), myocardial infarction (MI), unstable angina, New York Heart Association (NYHA) class III and IV heart failure and uncontrolled arrhythmia within the past 6 months. Rate-controlled arrhythmia may be eligible at the discretion of the Investigator.
5. Participant is considered a poor medical risk due to an uncontrolled medical disorder, non-malignant systemic disease, or active infection (including, r acute pelvic inflammatory disease), requiring intravenous antibiotics within the past 2 weeks. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).
6. Participant has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days before the study start.
7. Participant has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Use of inhaled steroids, local injection of steroids, and steroid eye drops are allowed.
8. Participant with severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2; COVID-19) influenza A/B within 3 months of screening.
9. Participant received a transfusion of blood products (including platelets or red blood cells) within 21 days prior to the first dose of the study drug.
10. Participant has undergone major surgery in the 4 weeks prior to consent.
11. Participant has -experienced any of the following with prior immunotherapy: any immune-related AE (irAE) of Grade 3 or higher, immune-related severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms \[DRESS\] syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary.)
12. Participant has taken part in a clinical trial of an investigational medical product or device within 30 days or 5 half-lives before study start, whichever comes later. \[except hormonal IUD\]
13. Participant has a concomitant malignancy, or participant has a prior non-endometrial invasive malignancy who has been disease-free for ≤5 years since end of treatment for the malignancy Non-melanoma skin cancer and definitively treated in-situ carcinomas is allowed.
14. Participant has a known history of Human Immunodeficiency Virus (HIV), or a positive test at screening.
15. Known active Hepatitis B or C, complete curative treatment and have no detectable viral RNA.
16. Participants are known to be hypersensitive to the active substance or any of the excipients.
17. Participant has a history or current diagnosis of interstitial lung disease.
18. Participant has received or is scheduled to receive, a live vaccine within 30 days before the first dose of study treatment, during study treatment, and for up to 180 days after receiving the last dose of study treatment.
19. Unwilling or unable to follow protocol requirements, including attendance at follow-up visit/s.
20. Participant has any condition contraindicated with tumor /blood sampling procedures required by the protocol.

Where this trial is running

Sydney, New South Wales and 2 other locations

• Westmead Hospital — Sydney, New South Wales, Australia (Not_yet_recruiting)
• Royal Brisbane and Women's Hospital — Brisbane, Queensland, Australia (Recruiting)
• Peter MacCallum Cancer Centre — Melbourne, Victoria, Australia (Recruiting)

Study contacts

• Study coordinator: Sara Baniahmadi

Conditions Endometrial Cancer Stage I; Mmr Deficiency; Endometrioid Endometrial Adenocarcinoma; Immune-related Adverse Event; Immunotherapy drug; Anti-programmed death receptor - 1