Durvalumab in HIV-1 Patients With Solid Tumors

Phase 2

Completed

• Conditions: HIV; Cancer
• Interventions: Drug: Durvalumab

• Registration Number: NCT03094286
• Lead Sponsor: Spanish Lung Cancer Group

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2017-03-10
• Study First Submitted QC: 2017-03-23
• Study First Posted: 2017-03-29
• Study Start: 2017-04-24
• Primary Completion: 2019-04-24
• Study Completion: 2022-03-22
• Results First Submitted: 2022-06-02
• Status Verified: 2024-01
• Results First Submitted QC: 2024-01-16
• Last Update Submitted: 2024-01-16
• Results First Posted: 2024-06-24
• Last Update Posted: 2024-06-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1	Durvalumab	Durvalumab (MEDI4736) monotherapy at the recommended dose of 1500mg every 4 weeks in solid tumors in HIV-1-infected patients

Primary Outcome Measures

Name	Time	Method
Best Response During the Treatment Period	From the first dose until last follow up, assessed up to 24 month	To explore the feasibility of durvalumab (MEDI4736) monotherapy at the recommended dose of 1500mg in solid tumors in HIV-1-infected patients The best overall response is a result of a combination of tumor responses in target and nontarget lesions according to Response Evaluation Criteria in Solid Tumors (RECIST).

Secondary Outcome Measures

Name	Time	Method
Duration of Response Global	From the time from first response evaluation to progression or death, assessed up to 24 months.	Only patients with best response Stable disease, Partial Response or Complete response during the treatment period are included in the response analysis.; Duration of response is the time from response (R) to progression/death (P/D).
Progression Free Survival (PFS)	From the date of randomization until end of follow up, assessed up to 24 months.	Defined as the length of time from the date of diagnose to the date of the first documented progression of disease. "Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions".A patient who does not progresses neither dies, is censored at the last tumor evaluation where no progression is detected.
Duration of Response- Dolutegravir/ no Dolutegravir	From the date of first response until progression or death, assessed up to 24 months.	Only patients with best response Stable disease, Partial Response or Complete response during the treatment period are included in the response analysis.; Duration of response is the time from response (R) to progression/death (P/D).
Duration of Response by Treatment With INSTIs or no INSTIs	From the date of the first response until progression or death, assessed up to 24 months	Only patients with best response Stable disease, Partial Response or Complete response during the treatment period are included in the response analysis.; Duration of response is the time from response to progression/death.
OS Analysis by PD-L1	OS is defined as the time from the inclusion date to the death, due to any cause. A patient who does not dies, is censored up to 24 months	Kaplan Meier method will be used to estimate the survival function. OS will be mesure at 24 months.
OS Analysis by Integrase Inhibitors	From the time from the inclusion date to the death, due to any cause. A patient who does not dies, is censored up to 24 months	OS is defined as the time from the inclusion date to the death, due to any cause. A patient who does not dies, is censored at the last contact date up to 24 months.
OS Analysis by Dolutegravir	From the time from the inclusion date to the death, due to any cause. A patient who does not dies, is censored up to 24 months	OS is defined as the time from the inclusion date to the death, due to any cause. A patient who does not dies, is censored up to 24 months
PFS Analysis by PD-L1	PFS is defined as the time from the inclusion date to the progression or death, due to any cause, up to 24 months patient who does not progresses neither dies, is censored at the last tumor evaluation where no progression is detected.	Progression Free Survival defined as the length of time from the date of diagnosis to the date of the first documented progression of disease
PFS Analysis by Dolutegravir	From the inclusion date to the progression or death, due to any cause, assessed up to 24 months.	PFS is defined as the time from the inclusion date to the progression or death, due to any cause, date.
PFS Analysis by Integrase Inhibitors	From the inclusion date to the progression or death, due to any cause, up to 24 months. patient who does not progresses neither dies, is censored at the last tumor evaluation where no progression is detected.	Defined as the length of time from the date of diagnosis to the date of the first documented progression of disease

Trial Locations

Locations (8)

H. La Paz; 🇪🇸 Madrid, Spain

Hospital La Fe; 🇪🇸 Valencia, Spain

Hospital Virgen del Rocío; 🇪🇸 Sevilla, Spain

H. Clínic i Provincial de Barcelona; 🇪🇸 Barcelona, Spain

Hospital Puerta de Hierro; 🇪🇸 Madrid, Spain

Consorci Sanitari de Terrassa; 🇪🇸 Terrassa, Barcelona, Spain

H. Universitario Quirón Dexeus; 🇪🇸 Barcelona, Spain

ICO-Badalona; 🇪🇸 Badalona, Barcelona, Spain