Durvalumab in HIV-1 Patients With Solid Tumors

The proposal is a phase II clinical study designed to assess the feasibility of durvalumab (MEDI4736) in HIV-1-infected individuals with solid tumors. Additionally, to obtain data that lets understand the possible benefit of this treatment in cancer patients and HIV infection, exploring if activity of durvalumab (MEDI4736) could be higher in cancer that has been produced at least in part due to the chronic immunosupression. Simultaneously, it will allow us to investigate the effect of disrupting this immunoregulatory pathway might have in reversing cancer pathways and HIV-specific T-cell function during persistent chronic HIV infection in humans.

PD-1/ PD-L1 coinhibitory pathway plays a significant role in the regulation of the immune response in both chronic infectious diseases and cancer.

Preclinical and animal data support the safety and promising activity of anti-PD-1 antibody in HIV-1 infection.

Demonstrated anticancer activity and safety profile of durvalumab (MEDI4736) in cancer clinical trials.

Unlikely drug interactions of durvalumab (MEDI4736) and antiretroviral treatments.

The proposal is a phase II clinical study designed to assess the feasibility of durvalumab (MEDI4736) in HIV-1-infected individuals with solid tumors. Additionally, to obtain data that lets understand the possible benefit of this treatment in cancer patients and HIV infection, exploring if activity of durvalumab (MEDI4736) could be higher in cancer that has been produced at least in part due to the chronic immunosupression. Simultaneously, it will allow us to investigate the effect of disrupting this immunoregulatory pathway might have in reversing cancer pathways and HIV-specific T-cell function during persistent chronic HIV infection in humans.

In this regard, our hypothesis is:

HIV patients with cancer have a similar outcome in terms of tolerability when treated with durvalumab (MEDI4736) monotherapy at the recommended dose than non HIV infected patients.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent
2. Age \> 18 years at time of study entry.
3. Eastern Cooperative Oncology Group (ECOG) 0-2
4. Life expectancy of \> 16 weeks
5. Adequate normal organ and marrow function.
6. Female subjects must either be of non-reproductive potential
7. Subject is willing and able to comply with the protocol
8. Subjects with histologically or cytologically advanced/metatasic-documented lung cancer, head and neck cancer, cervical cancer, melanoma, anal cancer, pancreatic cancer, gastrio-esophageal cancer, triple negative breast cancer, bladder or renal cancer, Cholangiocarcinoma, Kaposi sarcoma, lymphomas, ovarian cancer or Merkel cell carcinoma or any other tumor type in which anti PD-L1 antibodies have desmonstrated antitumoral activity, refractory to standard treatment, intolerant of standard treatment, or for which no standard therapy exists or who refuse the standard treatment.
9. Subjects may be included irrespectively of number of previous lines of treatment for advanced disease.
10. Prior palliative radiotherapy must have been completed at least 2 weeks prior to start the study treatment (subjects may receive localized palliative radiotherapy while receiving study drug).
11. Documented HIV-1 infection.
12. Undetectable viral load in the last analysis.
13. Subjects with brain metastases are eligible if they are asymptomatic, are treated or are neurological stable for at least 2 weeks without the use of steroids or on stable or decreasing dose of\<10mb daily prednisone or equivalent.
14. Subjects must be following an antiretroviral therapy at the moment of the inclusion.

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study. Previous enrollment in the present study.
2. Participation in another clinical study within last 4 weeks.
3. Other untreated coexisting HIV related malignancies.
4. Any previous treatment with a PD1, PD-L1 or PD-L2 inhibitor, including durvalumab.
5. Receipt of the last dose of anti-cancer therapy within 28 days prior to the first dose of study drug.
6. Mean QT interval corrected for heart rate (QTc) ≥470 ms
7. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab,
8. Any unresolved toxicity (CTCAE grade 2) from previous anti-cancer therapy.
9. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \>Grade 1.
10. Active or prior documented autoimmune disease within the past 2 years
11. Any syndrome that requires systemic corticosteroid/immunosuppressive medications
12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
13. History of primary immunodeficiency.
14. History of allogeneic organ transplant.
15. History of hypersensitivity to durvalumab or any excipient.
16. Uncontrolled intercurrent illness
17. Known history of active tuberculosis.
18. Any serious or uncontrolled medical disorder or active infection non HIV, that would impair the ability of the subject to receive the treatment of protocol therapy under treating physician criteria.
19. Subjects with previous malignances, are excluded unless a complete remission was achieved at least 5 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
20. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab.
21. Female subjects who are pregnant, breast-feeding, male, or female patients of reproductive potential who are not employing an effective method of birth control.
22. Symptomatic or uncontrolled brain metastases
23. Subjects with uncontrolled seizures.
24. Patients with tumoral disease in the head and neck region, such as peritracheal or periesophageal lymph node involvement,
25. Patients with neuroendocrine tumors of pulmonary origin or pulmonary metastases with evidence of active bleeding
26. Patients with digestive bleeding