Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies
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| ClinicalTrials.gov Identifier: NCT04287868 |
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Recruitment Status :
Active, not recruiting
First Posted : February 27, 2020
Last Update Posted : January 25, 2023
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Background:
More than 30,000 cases of human papillomavirus (HPV) associated cancers occur annually in the United States. When these cancers spread, they do not respond well to standard treatments and are often incurable. Researchers want to see if a mix of drugs can help.
Objective:
To learn if a mix of immunotherapy drugs can shrink tumors in people with HPV associated cancers.
Eligibility:
People ages 18 and older with locally advanced or metastatic HPV associated cancer, such as cervical cancers; P16+ oropharyngeal cancers; anal cancers; vulvar, vaginal, penile, and squamous cell rectal cancers; or other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are known HPV+ cancers
Design:
Participants will be screened with:
- medical history
- disease confirmation (or tumor biopsy)
- physical exam
- body scans (CT, MRI, and/or nuclear)
- blood tests
- electrocardiogram (to measure the electrical activity of the heart)
- urine tests.
Participants will get PDS0101 injected under the skin every 4 weeks for 6 doses. Then they will get it every 3 months for 2 doses.
Participants will get M7824 by intravenous infusion every 2 weeks. For this, a needle is inserted into a vein. The drug is given over a 1-hour period.
Participants will get NHS-IL12 injected under the skin every 4 weeks.
Participants will get the study drugs for up to 1 year. They will visit the NIH every 2 weeks. They will repeat the screening tests during the study.
About 28 days after treatment ends, participants will have a follow-up visit or telephone call. Then they will be contacted every 3 months for 1 year, and then every 6 months after that, for the rest of their life.
Patients with cervical cancer with prior pelvic radiation and boost brachytherapy will be enrolled in a separate cohort to evaluate safety and preliminary evidence of efficacy...
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Cervical Cancer HPV Cancers Anal Cancer Oropharyngeal Cancer Vulvar, Vaginal, Penile, Rectal Cancer | Biological: PDS0101 Biological: M7824 Biological: NHS-IL12 | Phase 1 Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 51 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Sequential Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I/II Trial of Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies |
| Actual Study Start Date : | June 9, 2020 |
| Estimated Primary Completion Date : | June 30, 2023 |
| Estimated Study Completion Date : | January 1, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm 1
Triple Therapy: PDS0101 + NHS-IL12 + M7824; The dose level of NHS-IL12 may decrease depending on DLT events. The dose level of HVP vaccine and M7824 will remain constant.
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Biological: PDS0101
PDS0101 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. Subcutaneous 1.0mL (2.4mg of total peptide and 3 mg of R-DOTAP) injection. Biological: M7824 M7824 will be administered at a flat dose of 1,200 mg IV (over 1 hour) once every 2 weeks. Biological: NHS-IL12 NHS-IL12 will be administered at as dose of potentially de-escalating doses by SC injection every 4 weeks. |
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Experimental: Arm 2
Triple Therapy: PDS0101 + NHS-IL12 + M7824; Accrual will be expanded first to 8 participants and then to 20 evaluable participants at the dose level selected in Arm 1 if more than 3 of 8 participants have an objective response.Triple Therapy: PDS0101 + NHS-IL12 + M7824; Reduced doses.
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Biological: PDS0101
PDS0101 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. Subcutaneous 1.0mL (2.4mg of total peptide and 3 mg of R-DOTAP) injection. Biological: M7824 M7824 will be administered at a flat dose of 1,200 mg IV (over 1 hour) once every 2 weeks. Biological: NHS-IL12 NHS-IL12 will be administered at as dose of potentially de-escalating doses by SC injection every 4 weeks. |
- Evaluate ORR of the combination of HPV vaccine, NHS-IL12, and M7824 in subjects with advanced HPV associated malignancies. [ Time Frame: one year ]Best treatment combination for participants with advanced or metastatic HPV associated malignancies.
- Safety [ Time Frame: One year ]Evaluate the safety of PDS0101, NHS-IL12, and M7824 in combination for participants with advanced or metastatic HPV associated malignancies.
- Progression-Free Survival Time [ Time Frame: Study End ]Assess progression-free survival time (PFS) according to RECIST 1.1.
- Overall Survival [ Time Frame: Study End ]Assess overall survival (OS).
- Adverse Events [ Time Frame: Study End ]To assess duration of response and ratio of participants that are hospitalized because of adverse events attributed to disease progression.
- Safety of reduced dose level in specific cervical cancer patients [ Time Frame: One year ]Determine safety of reduced dose level in cervical cancer patients with prior pelvic radiation and boost brachytherapy where a potential higher risk of grade 3 hematuria may exist with the full starting doses of the study drugs.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
- INCLUSION CRITERIA:
Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies:
- Cervical cancers;
- P16+ Oropharyngeal cancers;
- Anal cancers;
- Vulvar, vaginal, penile, and squamous cell rectal cancers;
- Other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are known HPV+.
Subjects must have measurable disease, per RECIST 1.1.
Subjects must have received one prior line of systemic chemotherapy as well as checkpoint therapy if checkpoint therapy is FDA approved for that specific tumor type (e.g., HNSCC and PDL1+ cervical cancer). Prior checkpoint therapy is not needed where checkpoint therapy has not been FDA approved for that specific tumor type (e.g. anal, vaginal, vulvar, penile, PDL1 negative cervical). Exceptions to the above include participant who are not eligible to receive the above therapies or who decline these standard treatment options after appropriate counseling has been provided. t.
Age >= 18 years.
ECOG performance status <= 2.
Adequate hematologic function at screening, as follows:
- Absolute neutrophil count (ANC) >=1 x 10^9/L;
- Hemoglobin >= 9 g/dL;
- Platelets >=75,000/microliter.
Adequate renal and hepatic function at screening, as follows:
- Serum creatinine <= 1.5 x upper limit of normal (ULN) OR Measured or calculated creatinine clearance >=40 mL/min for participant with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine or CrCl);
- Bilirubin <= 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin <= 3.0 x ULN;
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN, unless liver metastases are present, then values must be <= 3 x ULN).
The effects of the immunotherapies on the developing human fetus are unknown. For this reason and because immunotherapeutic agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for two months after study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
Participants serologically positive for HIV, Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative PCR. HIV positive participants must have CD4 count >= 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy for at least 4 weeks and have no reported opportunistic infections or castleman s disease within 12 months prior to enrollment.
Ability of subject to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
Participants with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the participant is otherwise suitable for enrollment. Partaicipants may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g. breast cancer).
Known intolerance to or life threatening side effects resulting from prior checkpoint inhibitor therapy.
Major surgery within 28 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).
Known active brain or central nervous system metastasis (less than a month out from definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (<3 months) or clinically significant cerebrovascular accident (<3 months). In order to be eligible participant must have repeat CNS imaging at least a month after definitive treatment showing stable CNS disease. Participants with evidence of intratumoral or peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is grade <= 1 and has been shown to be stable on two consecutive imaging scans.
Pregnant women are excluded from this study because these drugs have not been tested in pregnant women and there is potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these immunotherapies, breastfeeding should be discontinued if the mother is treated on this protocol.
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with exception of:
- Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or other mild autoimmune disorders not requiring immunosuppressive treatment;
- Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses <= 10 mg of prednisone or equivalent per day;
- Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable;
- Subjects on systemic intravenous or oral corticosteroid therapy with the exception of physiologic doses of corticosteroids (<= the equivalent of prednisone 10 mg/day) or other immunosuppressives such as azathioprine or cyclosporin A are excluded on the basis of potential immune suppression. For these subjects these excluded treatments must be discontinued at least 1 weeks prior to enrollment for recent short course use (<= 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (> 14 days). In addition, the use of corticosteroids as premedication for contrast- enhanced studies is allowed prior to enrollment and on study.
Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events, or other illness considered by the Investigator as high risk for investigational drug treatment.
Subjects unwilling to accept blood products as medically indicated.
History of non-HPV associated second malignancy within 3 years of enrollment except localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g,, low risk CCL). Patients taking adjuvant hormonal therapy for definitively treated cancers (e.g. breast cancer) are eligible.
Subjects with a known severe hypersensitivity reaction to a monoclonal antibodies (grade >/= 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to enrollment.
Receipt of prior lymphodepleting chemotherapy (e.g. cyclophosphamide, fludarabine) or any organ transplantation requiring ongoing immunosuppression.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04287868
| United States, Maryland | |
| National Institutes of Health Clinical Center | |
| Bethesda, Maryland, United States, 20892 | |
| Principal Investigator: | Julius Y Strauss, M.D. | National Cancer Institute (NCI) |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT04287868 |
| Other Study ID Numbers: |
200045 20-C-0045 |
| First Posted: | February 27, 2020 Key Record Dates |
| Last Update Posted: | January 25, 2023 |
| Last Verified: | January 23, 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.@@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) |
| Time Frame: | Clinical data available during the study and indefinitely. @@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active. |
| Access Criteria: | Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians. |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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HPV Cancers HPV Associated Malignancies Vaccine Immunotherapy Immuno-oncology |
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Neoplasms Anus Neoplasms Oropharyngeal Neoplasms Rectal Neoplasms Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases |
Gastrointestinal Diseases Intestinal Diseases Rectal Diseases Anus Diseases Pharyngeal Neoplasms Otorhinolaryngologic Neoplasms Head and Neck Neoplasms Pharyngeal Diseases Stomatognathic Diseases Otorhinolaryngologic Diseases |