Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies

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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

Brief Summary

      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...
    

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%) participants 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.

      Objective:

      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 checkpoint naive 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 participant declines standard
      treatment after appropriate counseling has been provided.

      Subjects must have measurable disease.

      Design:

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

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

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

      The first six participants will be evaluable for dose limiting toxicities (DLTs) and accrual
      will only continue to 8 participants who have not been treated with checkpoint inhibitors if
      less than 2 out of the first 6 participants experience a DLT.

      If three or more out of eight participants who have not been treated with checkpoint
      inhibitors have objective responses accrual will be expanded to enroll 20 evaluable
      participants.

      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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Evaluate ORR of the combination of HPV vaccine, NHS-IL12, and M7824 in subjects with advanced HPV associated malignancies.

Secondary Outcome

 Safety

Condition

Cervical Cancer

Intervention

PDS0101

Study Arms / Comparison Groups

 Arm 1
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

21

Start Date

June 9, 2020

Completion Date

January 1, 2023

Primary Completion Date

January 30, 2022

Eligibility Criteria

        -  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 prior first line systemic therapy unless the participant
             is not eligible to receive standard therapy or declines standard treatment.

          -  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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Julius Y Strauss, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04287868

Organization ID

200045

Secondary IDs

20-C-0045

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Julius Y Strauss, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

August 2021