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HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PDL1/TGF-Beta Trap (M7824) in Subjects With HPV Associated Cancers

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ClinicalTrials.gov Identifier: NCT04432597
Recruitment Status : Recruiting
First Posted : June 16, 2020
Last Update Posted : August 14, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

For some cancers associated with human papillomavirus (HPV), standard treatments are not helpful. Researchers want to see if a vaccine for HPV combined with a drug called M7824 has a better effect on these cancers than when they work alone.

Objective:

To find a safe dose of HPV vaccine alone or combined with M7824. Also, to test if either HPV vaccine alone or combined with M7824 causes a better immune response.

Eligibility:

People ages 18 and older with locally advanced or metastatic HPV associated cancer (Phase I) or stage II or III p16-positive oropharyngeal cancer (Phase II)

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Possible photos of skin lesions

CT, MRI, or nuclear bone scan: Participants will lie in a machine that takes pictures of the body. For the CT scan, they may have a contrast agent injected into a vein.

Participants may have up to 2 tumor biopsies. For participants in Phase II, this may be performed with a thin tube placed through the nose into the airway.

Participants will receive the HPV vaccine alone or with M7824. For participants on the Phase II, they will receive two doses of HPV vaccine under the skin either alone or with M7824 as an infusion spaced two weeks apart. This will be done prior to their planned chemoradiation or surgery. For participants on the Phase I, they will get the HPV vaccine injected under the skin 2 to 3 times in the first month. Then they will have a booster every 4 weeks. They will receive M7824 as an infusion into a vein every 2 weeks. Treatment will last up to 1 year.

After they stop treatment, participants will have a visit within 4 weeks. They will then be contacted for long-term follow-up every year, for the rest of their lives.

...


Condition or disease Intervention/treatment Phase
HPV Positive Cancer Vulvar, Vaginal, Penile, Rectal Cancer Anal Cancer Oropharyngeal Cancer Cervical Cancer Biological: PRGN-2009 Biological: M7824 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PD-L1/TGF-Beta Trap (M7824) in Subjects With HPV Positive Cancers
Actual Study Start Date : August 11, 2020
Estimated Primary Completion Date : October 1, 2023
Estimated Study Completion Date : October 1, 2023


Arm Intervention/treatment
Experimental: 1/Arm 1A
HPV vaccine at 1x10(11) Viral Particles (VP) (DL1) and at 5x10(11) VP (DL2)
Biological: PRGN-2009
On the phase I portion of the protocol PRGN-2009 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose patients will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.

Experimental: 2/Arm 1B
HPV vaccine at RP2D plus M7824 at 1200 mg
Biological: PRGN-2009
On the phase I portion of the protocol PRGN-2009 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose patients will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.

Biological: M7824
Subjects enrolled to Arms 1B and 2B will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is over 50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.

Experimental: 3/Arm 2A
HPV vaccine at RP2D given as neoadjuvant or induction therapy
Biological: PRGN-2009
On the phase I portion of the protocol PRGN-2009 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose patients will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.

Experimental: A/Arm 2B
HPV vaccine at RP2D plus M7824 at 1200 mg given as neoadjuvant or induction therapy
Biological: PRGN-2009
On the phase I portion of the protocol PRGN-2009 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose patients will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.

Biological: M7824
Subjects enrolled to Arms 1B and 2B will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is over 50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.




Primary Outcome Measures :
  1. Safety and recommended phase II dose of PRGN-2009 [ Time Frame: one year ]
    Phase I: In patients with recurrent/metastatic HPV positive cancer - To determine the safety and recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone or in combination with M7824 administered at RP2D of 1200 mg q2w.

  2. Level increase in CD3+ tumor infiltrating T cells post-treatment compared to pretreatment [ Time Frame: one year ]
    Phase II: In patients with newly diagnosed stage II/III p16-positive oropharyngeal cancer - To determine if either HPV vaccine alone (Arm 2A) or in combination with M7824 (Arm 2B) is able to result in a equal to or greater than 2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pretreatment.


Secondary Outcome Measures :
  1. overall response rate (ORR) [ Time Frame: study end ]
    Phase 1: To assess overall response rate (ORR) according to RECIST 1.1.

  2. progression-free survival time (PFS) [ Time Frame: study end ]
    Phase 1: To assess progression-free survival time (PFS).

  3. overall survival (OS) [ Time Frame: study end ]
    Phase 1: To assess overall survival (OS).

  4. duration of response [ Time Frame: study end ]
    Phase 1: To assess duration of response.

  5. ratio of patients that are hospitalized because of adverse events attributed to disease progression [ Time Frame: study end ]
    Phase 1: To assess ratio of patients that are hospitalized because of adverse events attributed to disease progression.

  6. increase in CD3+ tumor infiltrating lymphocytes [ Time Frame: study end ]
    Phase II: To determine if the rate of 2-fold increase in CD3+ tumor infiltrating lymphocytes (TILs) by immunohistology following PRGN-2009 in combination with M7824 (Arm 2B) is significantly more than the rate with PRGN-2009 alone (Arm 2A).

  7. does the use of PRGN-2009 alone or in combination with M7824 result in significantly prolonged survival [ Time Frame: study end ]
    Phase II: To determine if the use of PRGN-2009 alone or in combination with M7824 results in significantly prolonged survival as compared to the expected 80% three-year historical survival for this population.

  8. 3-year overall and relapse free survival rate for PRGN-2009 alone or PRGN-2009 plus M7824 [ Time Frame: study end ]
    year overall and relapse-free survival rate for PRGN-2009 alone (Arm 2A) or PRGN-2009 plus M7824 (Arm 2B) as neoadjuvant/ induction therapy before definitive standard of care therapy.

  9. assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone or in combination with the RP2D of M7824 [ Time Frame: study end ]
    Phase II: To assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone or in combination with the RP2D of M7824 in this patient population.



Information from the National Library of Medicine

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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:
  • Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies (Phase I only):

    • 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 with cytologically or histologically confirmed newly diagnosed stage II or III p16-positive oropharyngeal squamous cell carcinoma planned for definitive therapy (Phase II only).
  • Subjects must have measurable disease, per RECIST 1.1.
  • Subjects must have received prior standard systemic therapy unless the patient is not eligible to receive standard therapy or declines standard treatment (Phase I only). Specifically, for patients enrolled to the phase I portion of the study with oropharyngeal cancer patients should have previously received platinum based chemotherapy and PD(L)1 inhibitor based therapy, for patients with enrolled to the phase I portion of the study with cervical, anal or penile cancer patients should have previously received platinum based chemotherapy, for other rare HPV associated cancers where standard of care first line therapy does not exist (e.g., vulvar, vaginal) prior first line therapy is not required.
  • Men or Women; Age >=18 years.
  • ECOG performance status =< 2
  • Adequate hematologic function at screening, as follows:

    • Absolute neutrophil count (ANC) >=1 x 109/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 (PRGN-2009 vaccine and M7824) on the developing human fetus are unknown. For this reason and because M7824 and PRGN-2009 used in this trial are possibly 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 up to 2 months following the last dose of M7824 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.
  • 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:

  • Patients with prior investigational drug, live vaccine, 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).
  • 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 patients must have repeated 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.
  • Pregnant women are excluded from this study because M7824 and PRGN-2009 vaccine 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;
    • 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 immunosuppressors 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, known left ventricular ejection fraction <50% (confirmation of EF > 50% is not required for eligibility), history of myocarditis, or recent myocardial infarction (within 6 months), or other illness considered by the Investigator as high risk for M7824 drug treatment.

History of second malignancy within 3 years of enrollment except for the following: adequately treated localized skin cancer, cervical carcinoma in situ, superficial bladder cancer, other localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk CLL). For patients enrolled on the phase I portion of the protocol a second HPV driven malignancy is allowed.

  • Subjects with a known severe hypersensitivity reaction to monoclonal antibodies or its excipients (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.
  • For patients who may receive M7824, previous life-threatening side effects resulting from prior checkpoint inhibitor therapy.
  • Subject with pulse oximetry < 92% on room air at screening.
  • Participants unable to provide informed consent.
  • Participants whose inclusion in the trail would in the judgement of the PI lead to time

from diagnosis to initiation of curative treatment of >70 days (Arms 2A and 2B only).


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): NCT04432597


Contacts
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Contact: NCIMO Referral Office (240) 760-6050 ncimo_referrals@mail.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: NCT04432597    
Other Study ID Numbers: 200104
20-C-0104
First Posted: June 16, 2020    Key Record Dates
Last Update Posted: August 14, 2020
Last Verified: August 10, 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 Associated Malignancy
Immunotherapy
HPV Vaccine
PRGN-2009
M7824
Additional relevant MeSH terms:
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Anus Neoplasms
Oropharyngeal Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
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