Avelumab With Axitinib in Persistent or Recurrent Cervical Cancer After Platinum-based Chemotherapy

Avelumab With Axitinib in Persistent or Recurrent Cervical Cancer After Platinum-based Chemotherapy - a Proof-of-concept Study (ALARICE Study)

This is a single-arm, Simon's 2-stage, proof-of-concept trial. The aim is to evaluate the efficacy and safety of avelumab with axitinib in patients with persistent or recurrent cervical cancer following platinum-based chemotherapy. The study hypothesis is that the combination of avelumab and axitinib can significantly improve the objective response rate (ORR) with acceptable toxicity compared to traditional chemotherapy.

Cervical cancer is the fourth commonest female cancer in the world. When there is distant metastasis or recurrence, platinum-based chemotherapy is the usual treatment option. Once this first-line chemotherapy fails, the prognosis is dismal. Various second-line agents including second-line chemotherapy agents and immune checkpoint inhibitors have unsatisfactory response rate.

Inclusion Criteria:

1. Patients must be at least 18 years old.
2. Patients must have histologically confirmed cervical cancer, either squamous cell, adenocarcinoma or adenosquamous, that is either persistent or recurrent after at least one prior course of platinum-based chemotherapy. The platinum used in concurrent chemo-irradiation is not counted.
3. Patients should not be amenable to further surgery or radiotherapy except for the purpose of symptomatic relief.
4. Patients should have ECOG performance score 0 to 2.
5. Patients must have at least one target lesion by the RECIST 1.1 criteria.
6. Prior chemotherapy must have been completed at least 3 weeks before study drug administration, and all AEs have either returned to baseline or stabilized.
7. Prior systemic radiation therapy must have been completed at least 4 weeks before study drug administration. Prior focal radiotherapy must have completed at least 2 weeks before study drug administration.
8. Patients must have recovered from any major surgery that has been done at least 4 weeks before study drug administration.
9. Patients must have adequate bone marrow, renal, hepatic, thyroid and neurological function.
10. Patients should be willing to have blood tests where the blood will be used for biomarker studies.
11. Formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens of the primary tumors, should be available during screening. Alternatively, 15 unstained slides (6 minimum) will be acceptable.
12. Patients should agree for de novo biopsy if the tumors are at the cervix or vagina, or any other sites that are easy and safe to be biopsied. Tumors will be used for biomarker studies.
13. Patients who have childbearing potential should practice highly effective contraception throughout the study until at least 30 days after completion of the treatment

Exclusion Criteria:

1. Patients with concurrent malignancy within five years (except for basal or squamous cell skin cancer or in-situ breast cancer) are excluded.

2. Patients who have history of autoimmune diseases or other diseases requiring systemic steroid are excluded.

   Patients with vitiligo, type I diabetes mellitus, resolved asthma or atopy, stable autoimmune thyroid disease, eczema, psoriasis not requiring systemic treatment*, or not expected to recur in the absence of an external trigger are permitted to enroll.

3. Patients with the following past significant medical history in the last six months are excluded, such as pneumonitis, active or chronic viral hepatitis, cirrhosis, and inherited liver disease, myocardial infarction, unstable angina, unstable cardiac arrhythmia or clinically significant valvular heart diseases, CTCAE Grade 2 or greater peripheral vascular disease, active brain metastases or leptomeningeal metastases, uncontrolled seizures, subarachnoid hemorrhage, thromboembolic events.

4. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalents) or other immunosuppressive medications within 14 days of the start of treatment are excluded. Inhaled, local or topical steroids, systemic corticosteroids at physiologic doses, steroid used as pre-medication are allowed.

5. Patients with severe gastrointestinal conditions such as evidence of bowel obstruction or uncontrolled diarrhea in the last 4 weeks prior to enrollment, or history of inflammatory bowel disease, are not eligible.

6. Patients with uncontrolled hypertension (systolic >160mmHg or diastolic > 110mmHg) despite medication, active bleeding, bone fracture, unhealed wounds, clinically significant proteinuria (> 2g of protein over 24 hours), are excluded.

7. Patients with unhealed wounds include abdominal or pelvic fistula, gastrointestinal perforation or intra-abdominal abscess are excluded.

8. Patients having had severe infections within 4 weeks prior to the start of treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, and those who have active infection requiring systematic treatment, are excluded.

9. Patents with active tuberculosis, history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are excluded.

10. Patients who have suicidal ideations or behaviors requiring psychiatric intervention within 3 months prior to the start of treatment are excluded.

11. Patients who have history of severe (CTCAE Grade 3 or above) hypersensitivity reaction to any investigational products or any component in its formulations, and any monoclonal antibody, are excluded.

12. Patients who have known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the avelumab formulation.

13. Patients who have persisting toxicities related to previous therapy (NCI CTCAE v 5.0 Grade >1) are excluded. However, alopecia, Grade 2 or less sensory neuropathy, or other toxicities of Grade 2 or below that do not constitute a safety risk according to the investigators' judgment, are allowed.

14. Patients who have received prior immunotherapy, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, are excluded.

15. Patients who have received axitinib before are excluded.

16. Patients who received other anti-angiogenics within the last 6 months are excluded.

17. Patients with prior allogeneic stem cell or solid organ transplantation are excluded.

18. Use of other investigational drugs (drugs not marketed for any indication) within 28 days or at least 5 half-lives (whichever is longer) before the start of treatment, or during the course of this trial, is not allowed.

19. Use of any live attenuated vaccines against infectious diseases (e.g. influenza, varicella, etc.) within 4 weeks (28 days) of the start of treatment and during the study therapy is not allowed.

20. Patients with major operation within 28 days or open biopsy within 7 days before enrolment are not eligible.

21. Patients planned to have major surgery during the course of the study are excluded.

22. Patients who are pregnant or breastfeeding are excluded.