Clinical Trials /

Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies

NCT04287868

Description:

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....

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies
  • Official Title: Phase I/II Trial of Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 200045
  • SECONDARY ID: 20-C-0045
  • NCT ID: NCT04287868

Conditions

  • Cervical Cancer
  • HPV Cancers
  • Anal Cancer
  • Oropharyngeal Cancer
  • Vulvar, Vaginal, Penile, Rectal Cancer

Interventions

DrugSynonymsArms
PDS0101Arm 1
M7824Arm 1
NHS-IL12Arm 1

Purpose

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....

Detailed Description

      Background:

        -  Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal,
           oropharyngeal cancers etc.) are poorly palliated by standard therapies. There is an
           unmet need for active treatments for these tumors.

        -  In a phase I trial of M7824 (NCT02517398) 15 out of 43 (34.9%) patients with HPV
           associated malignancies had radiographic tumor responses according to RECIST 1.1 or
           iRECIST.

        -  While the response rate observed with M7824 appears to be higher than single agent PD-1
           inhibitors alone (15-20%), the majority of patients with these diseases still do not
           seem to benefit from immunotherapy.

        -  Preclinical studies suggest that the use of a combination of multiple immunotherapy
           agents may have improved anti-tumor efficacy.

             -  Specifically, preclinical studies have shown that the combination of three
                immunotherapy agents (1) a therapeutic vaccine against HPV positive cancers
                (PDS0101), (2) a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824),
                and (3) a tumor targeted immunocytokine (NHS-IL12) produces greater anti-tumor
                activity than any single or dual combination of these agents.

      Objectives:

      - To evaluate the objective response rate (ORR) according to Response Evaluation Criteria
      (RECIST 1.1) of the combination of (1) a therapeutic vaccine against HPV positive cancers
      (PDS0101), (2) a tumor targeted immunocytokine (NHS-IL12) and (3) a bifunctional fusion
      protein targeting PD-L1 and TGF beta (M7824) in subjects with advanced HPV associated
      malignancies.

      Eligibility:

        -  Age >= 18 years old.

        -  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+.

        -  Prior first line systemic therapy is required unless the patient declines standard
           treatment after appropriate counseling has been provided.

        -  Subjects must have measurable disease.

        -  Prior checkpoint inhibitor use is excluded.

      Design:

        -  This is a phase I/II trial of combination immunotherapy.

        -  The trial will be conducted using a Simon optimal two-stage design.

        -  Patients will receive HPV vaccine + NHS-IL12 + M7824.

        -  The first six patient will be evaluable for dose limiting toxicities (DLTs) and accrual
           will only continue to 8 patients if less than 2 out of the first 6 pts experience a DLT.

        -  If three or more out of eight patients have objective responses accrual will be expanded
           to enroll 20 evaluable patients.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalTriple Therapy: PDS0101 + NHS-IL12 + M7824
  • PDS0101
  • M7824
  • NHS-IL12

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. 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+.

          2. Subjects must have measurable disease, per RECIST 1.1.

          3. Subjects must have received prior first line systemic therapy unless the patient is
             not eligible to receive standard therapy or declines standard treatment.

          4. Age >= 18 years.

          5. ECOG performance status <= 2.

          6. Adequate hematologic function at screening, as follows:

               -  Absolute neutrophil count (ANC) >=1 x 10^9/L;

               -  Hemoglobin >= 9 g/dL;

               -  Platelets >=75,000/microliter.

          7. 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).

          8. 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.

          9. Patients serologically positive for HIV, Hep B, Hep C are eligible as long as the
             viral loads are undetectable by quantitative PCR. HIV positive patients 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.

        EXCLUSION CRITERIA:

          1. Patients 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
             patient is otherwise suitable for enrollment. Patients may continue adjuvant hormonal
             therapy in the setting of a definitively treated cancer (e.g. breast cancer).

          2. Prior checkpoint inhibitor therapy.

          3. Major surgery within 28 days prior to the first drug administration (minimally
             invasive procedures such as diagnostic biopsies are permitted).

          4. 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 patients must have repeat CNS imaging at least a month after definitive
             treatment showing stable CNS disease. Patients 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.

          5. 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.

          6. 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.

          7. 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.

          8. 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.

          9. 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.

         10. Receipt of prior lymphodepleting chemotherapy (e.g. cyclophosphamide, fludarabine) or
             any organ transplantation requiring ongoing immunosuppression.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate ORR of the combination of HPV vaccine, NHS-IL12, and M7824 in subjects with advanced HPV associated malignancies.
Time Frame:One year
Safety Issue:
Description:Best treatment combination for patients with advanced or metastatic HPV associated malignancies.

Secondary Outcome Measures

Measure:Safety
Time Frame:One year
Safety Issue:
Description:Evaluate the safety of PDS0101, NHS-IL12, and M7824 in combination for patients with advanced or metastatic HPV associated malignancies.
Measure:Progression-Free Survival Time
Time Frame:Study End
Safety Issue:
Description:Assess progression-free survival time (PFS) according to RECIST 1.1.
Measure:Overall Survival
Time Frame:Study End
Safety Issue:
Description:Assess overall survival (OS).
Measure:Adverse Events
Time Frame:Study End
Safety Issue:
Description:To assess duration of response and ratio of patients that are hospitalized because of adverse events attributed to disease progression.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • HPV Cancers
  • HPV Associated Malignancies
  • Vaccine
  • Immunotherapy
  • Immuno-oncology

Last Updated

March 3, 2020