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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 1
- 主要终点
- Safety and recommended phase II dose of PRGN-2009
研究概览
简要总结
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 (MSB0011359C) 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
Computed tomography (CT), magnetic resonance imaging (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.
...
详细描述
Background
- Metastatic human papillomavirus (HPV) associated malignancies (cervical, anal, oropharyngeal cancers, etc.) are often incurable and poorly palliated by standard therapies.
- HPV-positive (p16+) oropharyngeal cancers are the most common HPV-associated malignancy in the United States and are increasing in incidence.
- Stage II and III HPV-positive oropharyngeal cancer is primarily treated with definitive therapy.
- Although the prognosis for stage I HPV+ oropharyngeal cancer is favorable, about 20 percent of patients with stage II disease and 35 percent of patients with stage III disease will die within four years.
- Attempts to de-intensify treatment of HPV-positive oropharyngeal cancer by replacing high-dose cisplatin with cetuximab concurrent with radiotherapy have failed.
- Induction and neoadjuvant immunotherapy are an area of active study in this type of cancer. The aims of induction immunotherapy are to induce antigen-specific immunity prior to definitive therapy and to reduce the risk of disease relapse for patients with stage II and III disease.
- Therapeutic vaccines targeting HPV alone or in combination with M7824 (MSB0011359C) (dual programmed death-ligand 1 (PD-L1) and transforming growth factor beta (TGF- beta) inhibitor) have demonstrated induction of HPV antigen-specific responses and tumor growth inhibition in multiple pre-clinical models of HPV-positive malignancy.
- In clinical studies done in the Center for Cancer Research (CCR), M7824 as monotherapy has produced a notable objective response rate (35-40%) for metastatic HPV + cancers including Oropharyngeal Squamous Cell Carcinoma (OPSCC) and preclinical studies support the addition of an investigational HPV vaccine with therapeutic intent (PRGN-2009, a gorilla adenoviral based vaccine) to further increase anti-tumor efficacy.
Objectives:
Phase I in participants with recurrent/metastatic HPV positive cancer:
-Primary objective: 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 every 2 weeks (q2w).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Subjects with cytologically or histologically confirmed locally advanced not amenable to potentially curative local therapies or metastatic human papillomavirus (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 or with newly diagnosed stage II or III or IVA or IVB HPV-positive sinonasal squamous carcinoma (HPV-SNSCC) eligible for primary surgery (Phase II only).
- •Subjects must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Phase 1 only).
- •Phase I only: Participants must have received one prior line of systemic chemotherapy in the recurrent/metastatic setting as well as checkpoint blockade therapy in tumors with Food and Drug Administration (FDA) approval (head and neck squamous cell cancer and programmed death-ligand 1 (PDL1+) cervical cancer). Exceptions to this include participants not eligible to receive standard therapy.
- •Men or Women; Age >=18 years.
- •Eastern Cooperative Oncology Group (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.
- •Participants serologically positive for human immunodeficiency virus (HIV), Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative polymerase chain reaction (PCR). HIV positive participants must have cluster of differentiation 4 (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.
排除标准
- •Participants 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 participant is otherwise suitable for enrollment. Participants 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 participants must have repeated central nervous system (CNS) imaging at least a month after definitive treatment showing stable CNS disease. Participants with evidence of intra-tumoral 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.
- •Only for Phase I, Arm 1B: 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.
- •Only for Phase I: 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 ejection fraction (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.
- •Only for Phase I: Subjects refusing to accept blood products as medically indicated.
- •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 chronic lymphocytic leukemia (CLL)). For participants enrolled on the phase I portion of the protocol a second HPV driven malignancy is allowed.
- •Only for Phase I, Arm 1B: Subjects with a known severe hypersensitivity reaction to monoclonal antibodies or its excipients (grade >/= 3 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v5) will be evaluated by the allergy/immunology team prior to enrollment.
- •Prior allogenic tissue/solid organ transplant.
- •For participants who may receive M7824: previous life-threatening side effects resulting from prior checkpoint inhibitor therapy.
- •Participants with pulse oximetry < 92% on room air at screening.
- •Participants unable to provide informed consent.
- •Participants whose inclusion in the trial would in the judgement of the principal investigator (PI) lead to time from diagnosis to initiation of curative treatment of>70 days (Arm 2A only).
研究组 & 干预措施
2/Arm 1B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.
干预措施: Brain MRI (Diagnostic Test)
3/Arm 2A
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) given as neoadjuvant or induction therapy.
干预措施: Biopsy (Procedure)
4/Arm 2B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.
干预措施: Brain MRI (Diagnostic Test)
2/Arm 1B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.
干预措施: PRGN-2009 (Biological)
2/Arm 1B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.
干预措施: M7824 (Biological)
2/Arm 1B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.
干预措施: EKG (Diagnostic Test)
2/Arm 1B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.
干预措施: Biopsy (Procedure)
2/Arm 1B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg.
干预措施: CT Scan (Diagnostic Test)
3/Arm 2A
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) given as neoadjuvant or induction therapy.
干预措施: CT Scan (Diagnostic Test)
3/Arm 2A
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) given as neoadjuvant or induction therapy.
干预措施: PRGN-2009 (Biological)
4/Arm 2B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.
干预措施: PRGN-2009 (Biological)
1/Arm 1A
Human Papillomavirus Vaccine (HPV) vaccine at 1x10(11) Viral Particles (VP) Dose Level 1 (DL1) and at 5x10(11) VP Dose Level 2 (DL2)
干预措施: PRGN-2009 (Biological)
4/Arm 2B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.
干预措施: M7824 (Biological)
1/Arm 1A
Human Papillomavirus Vaccine (HPV) vaccine at 1x10(11) Viral Particles (VP) Dose Level 1 (DL1) and at 5x10(11) VP Dose Level 2 (DL2)
干预措施: Biopsy (Procedure)
1/Arm 1A
Human Papillomavirus Vaccine (HPV) vaccine at 1x10(11) Viral Particles (VP) Dose Level 1 (DL1) and at 5x10(11) VP Dose Level 2 (DL2)
干预措施: EKG (Diagnostic Test)
3/Arm 2A
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) given as neoadjuvant or induction therapy.
干预措施: EKG (Diagnostic Test)
4/Arm 2B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.
干预措施: EKG (Diagnostic Test)
4/Arm 2B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.
干预措施: Biopsy (Procedure)
3/Arm 2A
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) given as neoadjuvant or induction therapy.
干预措施: Brain MRI (Diagnostic Test)
1/Arm 1A
Human Papillomavirus Vaccine (HPV) vaccine at 1x10(11) Viral Particles (VP) Dose Level 1 (DL1) and at 5x10(11) VP Dose Level 2 (DL2)
干预措施: CT Scan (Diagnostic Test)
1/Arm 1A
Human Papillomavirus Vaccine (HPV) vaccine at 1x10(11) Viral Particles (VP) Dose Level 1 (DL1) and at 5x10(11) VP Dose Level 2 (DL2)
干预措施: Brain MRI (Diagnostic Test)
4/Arm 2B
Human Papillomavirus Vaccine (HPV) vaccine at recommended phase 2 dose (RP2D) plus M7824 at 1200 mg given as neoadjuvant or induction therapy.
干预措施: CT Scan (Diagnostic Test)
结局指标
主要结局
Safety and recommended phase II dose of PRGN-2009
时间窗: one year
Phase I: In participants 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.
Level increase in CD3+ tumor infiltrating T cells post-treatment compared to pre-treatment
时间窗: one year
Phase II: In participants with newly diagnosed stage I (T1,T2 N1)/II/III p16-positive oropharyngeal cancer - To determine if HPV vaccine alone (Arm 2A) is able to result in a equal to or greater than 2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment in p16-positive oropharyngeal cancer.
Phase I: Recommended Phase II Dose of PRGN-2009
时间窗: Date treatment consent signed to date off study, approximately 18 months
Phase I: To determine the recommended phase II dose (RP2D) of PRGN-2009 Human Papillomavirus Vaccine (HPV) vaccine alone or in combination with M7824 (MSB0011359C). Recommended Phase 2 Dose, the dose of a drug or drug combination that was identified in a Phase 1 study (dose finding study) that was identified for continued study.
Phase I: Safety - Number of Treatment-related Serious Adverse Events (AE) of Grades 1, 2, 3, 4 and/or 5 Along With the AE Term
时间窗: Date treatment consent signed to date off study, an average of 6 months
Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. All participants who receive any investigational treatment will be evaluable for safety and toxicity evaluations.
Phase II: Percentage of Participants That Had a 2-fold Increase of Cluster of Differentiation 3 (CD3+) Tumor Infiltrating T Cells in Biopsies Performed Post-treatment Compared to Pre-treatment
时间窗: Pre-Treatment (Baseline) and anytime between Week 4-5 post treatment
CD3+ tumor infiltrating T cells post treatment compared with pre-treatment reported with a 95% confidence interval assessed by multiplex CD3+ tumor infiltrating lymphocytes assessed by multiplex immunofluorescence from the surgical/ biopsy tissue collected pre- and post-treatment. The percentage of participants with doubling of baseline CD3+ tumor infiltrating lymphocytes will be provided as well as the 95% confidence interval. The CD3 cells are assessed by multiplex immunofluorescence in the biopsies. Doubling is the desired outcome.
次要结局
- ratio of participants that are hospitalized because of adverse events attributed to disease progression(study end)
- does the use of PRGN-2009 alone result in significantly prolonged survival(study end)
- 3-year overall and relapse-free survival rate for PRGN-2009 alone(study end)
- progression-free survival time (PFS)(study end)
- overall survival (OS)(study end)
- duration of response(study end)
- assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone(study end)
- overall response rate (ORR)(study end)
- Phase I: Proportion of Participants That Are Hospitalized Because of Adverse Events Attributed to Disease Progression(Date treatment consent signed to date of progression, an average of 6 months)
- Phase II: 3-year Overall Survival for PRGN-2009 Alone(3 years)
- Phase II: 3 Year Relapse-free Survival for PRGN-2009 Alone(3 years)
- Phase I: Overall Survival (OS)(The time from the date of first treatment to the date of death (any cause), an average of 12 months)
- Phase I: Progression-free Survival Time (PFS)(Date of first treatment to date of disease progression or death (any cause), an average of 6 months)
- Phase I: Duration of Response (DOR)(Date of first treatment to date of disease progression or death (any cause), an average of 4 months)
- Phase II: Safety - Number of Treatment-related Serious Adverse Events (AE) of Grades 1, 2, 3, 4 and/or 5 Along With the AE Term(Date treatment consent signed up to 28 days after last treatment)
- Phase II: Overall Survival at 3 Years Compared With Historical Cohort(3 years)
- Phase I: Overall Response Rate (ORR)(study end, an average of 6 months)
研究者
Charalampos Floudas, MD, DMSc, MS
Principal Investigator
National Cancer Institute (NCI)