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Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04287868
Recruitment Status : Recruiting
First Posted : February 27, 2020
Last Update Posted : September 14, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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....


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

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 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 patient 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.
  • 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 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 : July 30, 2021
Estimated Study Completion Date : July 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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 16.8 (Micro)g/kg by SC injection every 4 weeks.

Experimental: Arm 2
Triple Therapy: PDS0101 + NHS IL12 + M7824; Accrual will be expanded first to 8 patients and then to 20 evaluable patients at the dose level selected in Arm 1 if more than 3 of 8 patients have an objective response.
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 16.8 (Micro)g/kg by SC injection every 4 weeks.




Primary Outcome Measures :
  1. 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 patients with advanced or metastatic HPV associated malignancies.


Secondary Outcome Measures :
  1. Safety [ Time Frame: One year ]
    Evaluate the safety of PDS0101, NHS-IL12, and M7824 in combination for patients with advanced or metastatic HPV associated malignancies.

  2. Progression-Free Survival Time [ Time Frame: Study End ]
    Assess progression-free survival time (PFS) according to RECIST 1.1.

  3. Overall Survival [ Time Frame: Study End ]
    Assess overall survival (OS).

  4. Adverse Events [ Time Frame: Study End ]
    To assess duration of response and ratio of patients that are hospitalized because of adverse events attributed to disease progression.



Information from the National Library of Medicine

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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Known intolerance to or life threatening side effects resulting from 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.

Information from the National Library of Medicine

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


Contacts
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Contact: Michell J Manu, R.N. (240) 760-7117 michell.manu@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Julius Y Strauss, M.D. National Cancer Institute (NCI)
Additional Information:
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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: September 14, 2020
Last Verified: September 8, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
HPV Cancers
HPV Associated Malignancies
Vaccine
Immunotherapy
Immuno-oncology
Additional relevant MeSH terms:
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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