Cancer, HIV
Conditions
Keywords
HIV, HIV with cancer patient, D006678
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.
Interventions
DRUGDurvalumab
Durvalumab monotherapy of 1500mg every 4 weeks in solid tumors in HIV-1-infected patients until progression significant clinical deterioration, unacceptable toxicity, any criterion for withdrawal from the trial or trial drug is fulfilled
Sponsors
Spanish Lung Cancer Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 50 mg/mL for intravenous(IV) administration
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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 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 |
| 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. |
| 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. |
Countries
Spain
Participant flow
Recruitment details
Between April 2017 and July 2018, a total of 20 patients were enrolled in the study from 7 different sites.
Pre-assignment details
Screening details: Histologically advanced/metatasic 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. HIV infection. Undetectable viral load at last test
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm Durvalumab (MEDI4736) monotherapy at the recommended dose of 1500mg every 4 weeks in solid tumors in HIV-1-infected patients
Durvalumab: Durvalumab monotherapy of 1500mg every 4 weeks in solid tumors in HIV-1-infected patients until progression significant clinical deterioration, unacceptable toxicity, any criterion for withdrawal from the trial or trial drug is fulfilled. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Experimental Arm |
|---|---|
| Age, Continuous | 53.50 years STANDARD_DEVIATION 10.5 |
| Basal CD4-count cells/mm3 <200 | 1 participants |
| Basal CD4-count cells/mm3 200-350 | 8 participants |
| Basal CD4-count cells/mm3 >350 | 11 participants |
| CD4 at baseline | 416.95 cells/mm^3 STANDARD_DEVIATION 181.27 |
| Distribution of time on treatment for patients with Integrase Inhibitors With Integrase Inhibitors | 10.90 Months STANDARD_DEVIATION 13.13 |
| Distribution of time on treatment for patients with Integrase Inhibitors Without Integrase Inhibitors | 3.67 Months STANDARD_DEVIATION 3.99 |
| ECOG ECOG 0-1 | 19 participants |
| ECOG ECOG 2 | 1 participants |
| HIV-1 group transmission Heterosexual individuals | 6 participants |
| HIV-1 group transmission IDUs | 6 participants |
| HIV-1 group transmission MSM | 6 participants |
| HIV-1 group transmission Unknown | 2 participants |
| Lung cancer type NSCLC EGFR-, ALK- | 14 participants |
| Lung cancer type Other | 5 participants |
| Lung cancer type SCLC | 1 participants |
| LungCancer(Y/N) No | 5 participants |
| LungCancer(Y/N) Yes | 15 participants |
| Metastasis by cancer type Anal | 2 participants |
| Metastasis by cancer type Bladder | 1 participants |
| Metastasis by cancer type Melanoma | 2 participants |
| Metastasis by cancer type NSCLC | 14 participants |
| Metastasis by cancer type SCLC | 1 participants |
| Nº of prior systemic therapies Equal or major of Two | 8 participants |
| Nº of prior systemic therapies None | 8 participants |
| Nº of prior systemic therapies One | 4 participants |
| NSCLC histology Adenocarcinoma | 8 participants |
| NSCLC histology N/A | 6 participants |
| NSCLC histology NOS/Undifferenciated | 3 participants |
| NSCLC histology Squamous | 3 participants |
| Number of metastatic sites Five | 2 participants |
| Number of metastatic sites One | 5 participants |
| Number of metastatic sites Three | 4 participants |
| Number of metastatic sites Two | 9 participants |
| Plasma Viral load at baseline | 25.39 copies/mL STANDARD_DEVIATION 15.58 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment Spain | 20 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 16 Participants |
| Smoking status Former smoker | 9 participants |
| Smoking status Never smoker | 2 participants |
| Smoking status Smoker | 9 participants |
| Time on treatment and PD-L1 PD-1 Negative | 5.97 Month STANDARD_DEVIATION 8.57 |
| Time on treatment and PD-L1 PD-1 Positive | 13.18 Month STANDARD_DEVIATION 6.14 |
| Time since cancer diagnosis | 1.80 years STANDARD_DEVIATION 2.8 |
| Time since HIV diagnosis | 17.68 years STANDARD_DEVIATION 10.18 |
| Treatment duration | 8.73 Month STANDARD_DEVIATION 11.57 |
| Type of Cancer Anal | 2 participants |
| Type of Cancer Bladder | 1 participants |
| Type of Cancer Melanoma | 2 participants |
| Type of Cancer NSCLC | 14 participants |
| Type of Cancer SCLC | 1 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 11 / 20 |
Outcome results
Primary
Best Response During the Treatment Period
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).
Time frame: From the first dose until last follow up, assessed up to 24 month
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Arm | Best Response During the Treatment Period | Stable disease | 5 participants |
| Experimental Arm | Best Response During the Treatment Period | Progression Disease | 7 participants |
| Experimental Arm | Best Response During the Treatment Period | Not Evaluated | 4 participants |
| Experimental Arm | Best Response During the Treatment Period | Complete Response | 1 participants |
| Experimental Arm | Best Response During the Treatment Period | Partial Response | 3 participants |
Secondary
Duration of Response by Treatment With INSTIs or no INSTIs
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.
Time frame: From the date of the first response until progression or death, assessed up to 24 months
Population: Descriptive analysis of response duration - INSTIs (Integrase Inhibitors) or no INSTIs (No Integrase Inhibitors) treated patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | Duration of Response by Treatment With INSTIs or no INSTIs | Integrase Inhibitors | 11.32 Month |
| Experimental Arm | Duration of Response by Treatment With INSTIs or no INSTIs | No Integrase Inhibitors | 2.10 Month |
Secondary
Duration of Response- Dolutegravir/ no Dolutegravir
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).
Time frame: From the date of first response until progression or death, assessed up to 24 months.
Population: Kaplan Meier Estimated median duration of response- Dolutegravir/ no Dolutegravir patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | Duration of Response- Dolutegravir/ no Dolutegravir | Dolutegravir | 27.4 Month |
| Experimental Arm | Duration of Response- Dolutegravir/ no Dolutegravir | No Dolutegravir | 2.8 Month |
Secondary
Duration of Response Global
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).
Time frame: From the time from first response evaluation to progression or death, assessed up to 24 months.
Population: Applying a Kaplan -Meyer model the median duration of response is estimated for each type of cancer
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Experimental Arm | Duration of Response Global | Anal | 3.78 Months | Standard Deviation 0 |
| Experimental Arm | Duration of Response Global | Melanoma | 7.39 Months | Standard Deviation 0 |
| Experimental Arm | Duration of Response Global | NSCLC | 3.7 Months | Standard Deviation 1.2 |
Secondary
OS Analysis by Dolutegravir
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
Time frame: 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
Population: Kaplan-Meier model- Summary results of OS- Strata patients treated with or without Dolutegravir
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | OS Analysis by Dolutegravir | Dolutegravir | 12.8 Month |
| Experimental Arm | OS Analysis by Dolutegravir | No Dolutegravir | 8.4 Month |
Secondary
OS Analysis by Integrase Inhibitors
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.
Time frame: 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
Population: Kaplan-Meier model- Summary results of OS- Strata Integrase Inhibitors
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | OS Analysis by Integrase Inhibitors | Integrase Inhibitors | 11.5 Months |
| Experimental Arm | OS Analysis by Integrase Inhibitors | No Integrase Inhibitors | 6.0 Months |
Secondary
OS Analysis by PD-L1
Kaplan Meier method will be used to estimate the survival function. OS will be mesure at 24 months.
Time frame: 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
Population: Kaplan-Meier model- Summary results of OS - Strata PD-L1 patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | OS Analysis by PD-L1 | PDL-1 positive | 18.9 Months |
| Experimental Arm | OS Analysis by PD-L1 | PDL-1 negative | 7.4 Months |
Secondary
PFS Analysis by Dolutegravir
PFS is defined as the time from the inclusion date to the progression or death, due to any cause, date.
Time frame: From the inclusion date to the progression or death, due to any cause, assessed up to 24 months.
Population: Effect of the presence of Dolutegravir, in the PFS in cancer patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | PFS Analysis by Dolutegravir | Dolutegravir | 4.2 Month |
| Experimental Arm | PFS Analysis by Dolutegravir | No Dolutegravir | 2.3 Month |
Secondary
PFS Analysis by Integrase Inhibitors
Defined as the length of time from the date of diagnosis to the date of the first documented progression of disease
Time frame: 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.
Population: Kaplan-Meier model- Summary results of PFS by the effect of the presence of Integrase Inhibitors
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | PFS Analysis by Integrase Inhibitors | Integrase Inhibitors | 2.5 Months |
| Experimental Arm | PFS Analysis by Integrase Inhibitors | No Integrase Inhibitors | 2.5 Months |
Secondary
PFS Analysis by PD-L1
Progression Free Survival defined as the length of time from the date of diagnosis to the date of the first documented progression of disease
Time frame: 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.
Population: Summary results Strata by PD-L1 results in cancer patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental Arm | PFS Analysis by PD-L1 | Negative PDL-1 | 2.3 Month |
| Experimental Arm | PFS Analysis by PD-L1 | Positive PDL-1 | 5.7 Month |
Secondary
Progression Free Survival (PFS)
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.
Time frame: From the date of randomization until end of follow up, assessed up to 24 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Progression Free Survival (PFS) | 2.5 Months |