TSR-042 as Maintenance Therapy for Patients With High-risk Locally Advanced Cervical Cancer After Chemo-radiation

A Randomized, Open Label, Phase II Trial of Anti-PD1, TSR-042, as Maintenance Therapy for Patients With High-risk Locally Advanced Cervical Cancer After Chemo-radiation

Patients with locally advanced cervical cancer (LACC) despite definitive chemo-radiotherapy, has a poor progression-free survival (PFS) and overall survival (OS). The hypothesis is that the use of TSR-042, checkpoint inhibitor, as consolidation therapy following concurrent chemo-radiation would increase PFS in these patients. The incorporation of immunotherapy after chemo-radiation is one the best scenarios for this approach, since takes advantages of "the ideal microenvironment" created after radiation. In a similar rationale, the phase 3 study that compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy, showed that progression-free survival was significantly longer with durvalumab than with placebo in all sub-groups regardless of response obtained to chemotherapy, namely patients with stable disease (SD) gained the same benefit that patients with partial response (PR). Due to the aforementioned biology of cervical cancer, the proven activity of anti programmed cell death protein 1 (Anti-PD1) agents in metastatic and/or recurrent cervical cancer and the poor PFS and OS in patients with LACC despite definitive chemo-radiotherapy, we consider to analyze the Anti-PD1 agent, TSR-042 as maintenance therapy after concurrent chemo-radiation (CCRT)

Inclusion Criteria:

1. Signed informed consent before any study-specific procedure

2. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1

3. Participant must be a female ≥ 18 years of age

4. Life expectancy ≥3 months

5. Participant must have biopsy-confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix.

6. Patients must have archival tumor tissue available that is formalin-fixed and paraffin embedded.

7. At diagnosis:

   • Federation of Gynecologists and Obstetricians (FIGO) stages IB2, IIA2, IIB with pelvic lymph node involvement: Biopsy-proven pelvic node involvement, 2 or more positive nodes by magnetic resonance imaging (MRI) or computed tomography (CT) (≥1.5 cm shortest dimension), 2 or more positive nodes by Positron Emission Tomography (PET) (with standardized uptake values (SUV) ≥2.5)
   • FIGO stages IIIA, IIIB, IVA
   • Any FIGO stage with para-aortic lymph node involvement: Biopsy-proven para-aortic node involvement, 1 or more positive nodes by MRI or CT (≥1.5 cm shortest dimension), 1 or more positive pelvic nodes by PET (with SUV ≥ 2.5)

8. Subjects must have received combination chemotherapy and radiotherapy (CCRT) with curative intent. Patients must have received at least 4 doses of weekly cisplatin.

9. Patients must have completed definitive treatment, namely chemo-radiation, up to 12 weeks prior to sign the Informed Consent form.

10. Toxicities resulting from chemo-radiation must resolve to ≤ Grade 1 prior to randomization.

11. Participant must have adequate organ function, defined as follows:

    • Absolute neutrophil count ≥ 1,500/µL
    • Platelets ≥ 100,000/µL
    • Hemoglobin ≥ 9 g/dL
    • Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min using Cockcroft-Gault equation for patients with creatinine levels > 1.5× institutional ULN
    • Total bilirubin ≤ 1.5× ULN OR direct bilirubin ≤ 1× ULN
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULN unless liver metastases are present, in which case they must be ≤ 5× ULN
    • International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

12. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

13. Negative Test Results for Hepatitis

14. Female participant has a negative serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 150 days after the last dose of study treatment, or is of nonchildbearing potential.

15. Participant must agree to not breastfeed during the study or for 150 days after the last dose of study treatment.

16. Male partners must agree to use an adequate method of contraception starting with the first dose of study treatment through 150 days after the last dose of study treatment.

17. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent

Exclusion Criteria:

1. Histological types other than in inclusion criteria, like sarcomas, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancers.
2. FIGO Stage IVB (cancer has spread distantly).
3. Subjects who have undergone a previous hysterectomy defined as removal of the entire uterus or will have a hysterectomy as part of their initial cervical cancer therapy.
4. Has not achieved at least a partial response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after completion of CCRT administered with curative intent.
5. Patients previously treated with chemotherapy except when used concurrently with radiation therapy. Patients who have received either concurrent paclitaxel with radiation therapy or carboplatin/paclitaxel as adjuvant therapy are ineligible for the study.
6. Prior treatment with any anti-vascular endothelial growth factor (anti-VEGF) drug, including bevacizumab, CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA 4.
7. Patients with a concomitant malignancy other than non-melanoma skin cancer.
8. History of autoimmune disease
9. History of idiopathic pulmonary fibrosis, organizing pneumonia , drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
10. History of interstitial lung disease.
11. Active tuberculosis.
12. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1.
13. Administration of a live, attenuated vaccine within 14 days before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.
14. Treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1.
15. Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1.
16. Women that are breastfeeding or pregnant.
17. Demonstration of any other disease, neurological or metabolic dysfunction, found upon physical examination or laboratory tests involving a reasonable suspicion of the existence of a disease or condition that contraindicates the use of an experimental drug, or that involves an increased risk to the patient of treatment-related complications.
18. No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment
19. Participant must not be simultaneously enrolled in any interventional clinical trial
20. Participant must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.
21. Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
22. Participant has had radiation therapy encompassing >20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
23. Participant must not have a known hypersensitivity to TSR-042 components or excipients.
24. Participant must not have a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
25. Participant must not have known, symptomatic brain or leptomeningeal metastases
26. Patient experienced ≥ Grade 3 immune-related adverse events (AE) with prior immunotherapy, with the exception of non-clinically significant lab abnormalities.
27. Participant has a known history of human immunodeficiency virus (type 1 or 2 antibodies).