Clinical Trials /

Stereotactic Body Radiation Therapy, Tremelimumab and Durvalumab in Treating Participants With Recurrent or Metastatic Cervical, Vaginal, or Vulvar Cancers

NCT03452332

Description:

This phase I trial studies how well stereotactic body radiation therapy works in combination with tremelimumab and durvalumab in treating participants with cervical, vaginal, or vulvar cancers that have come back (recurrent) or spread to other areas of the body (metastatic). Stereotactic body radiation therapy is a specialized radiation therapy that sends x-rays directly to the tumor using smaller doses over several days and may cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as tremelimumab and durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy, tremelimumab, and durvalumab may work better in treating participants with cervical, vaginal, or vulvar cancers.

Related Conditions:
  • Cervical Carcinoma
  • Vaginal Carcinoma
  • Vulvar Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Stereotactic Body Radiation Therapy, Tremelimumab and Durvalumab in Treating Participants With Recurrent or Metastatic Cervical, Vaginal, or Vulvar Cancers
  • Official Title: Phase I Multi-Center Study of Stereotactic Ablative Radiotherapy (SABR) in Combination With Durvalumab and Tremelimumab in Patients With Recurrent/Metastatic Advanced Cervical, Vaginal, or Vulvar Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2017-0548
  • SECONDARY ID: NCI-2018-00627
  • SECONDARY ID: 2017-0548
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03452332

Conditions

  • Human Papillomavirus Positive
  • Human Papillomavirus-Related Cervical Squamous Cell Carcinoma
  • Human Papillomavirus-Related Vulvar Squamous Cell Carcinoma
  • Metastatic Cervical Adenocarcinoma
  • Metastatic Cervical Carcinoma
  • Metastatic Cervical Squamous Cell Carcinoma, Not Otherwise Specified
  • Metastatic Vaginal Adenocarcinoma
  • Metastatic Vaginal Carcinoma
  • Metastatic Vulvar Carcinoma
  • Recurrent Cervical Carcinoma
  • Recurrent Vaginal Carcinoma
  • Recurrent Vulvar Carcinoma
  • Stage IV Cervical Cancer AJCC v8
  • Stage IV Vaginal Cancer AJCC v8
  • Stage IV Vulvar Cancer AJCC v8
  • Stage IVA Cervical Cancer AJCC v8
  • Stage IVA Vaginal Cancer AJCC v8
  • Stage IVA Vulvar Cancer AJCC v8
  • Stage IVB Cervical Cancer AJCC v8
  • Stage IVB Vaginal Cancer AJCC v8
  • Stage IVB Vulvar Cancer AJCC v8
  • Vaginal Squamous Cell Carcinoma, Not Otherwise Specified
  • Vulvar Adenocarcinoma

Interventions

DrugSynonymsArms
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Treatment (tremelimumab, durvalumab, SABR)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabTreatment (tremelimumab, durvalumab, SABR)

Purpose

This phase I trial studies how well stereotactic body radiation therapy works in combination with tremelimumab and durvalumab in treating participants with cervical, vaginal, or vulvar cancers that have come back or spread to other areas of the body. Stereotactic body radiation therapy is a specialized radiation therapy that sends x-rays directly to the tumor using smaller doses over several days and may cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as tremelimumab and durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy, tremelimumab, and durvalumab may work better in treating participants with cervical, vaginal, or vulvar cancers.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety, and tolerability of combined immune checkpoint blockade with 3
      fractions of stereotactic body radiation therapy (stereotactic ablative radiotherapy [SABR])
      of up to two metastatic lesions in patients with recurrent and or metastatic cervical,
      vaginal, or vulvar cancer.

      SECONDARY OBJECTIVES:

      I. To evaluate clinical response rates and assess toxicities of treatment to durvalumab
      combined with tremelimumab with 3 fractions of SABR of at least one and up to two metastatic
      lesions in patients with recurrent/metastatic cervical, vaginal, or vulvar cancer.

      II. To estimate progression-free survival, overall survival, and time to next treatment.

      III. Evaluate biomarkers of response to immune checkpoint inhibition combined with SABR in
      biopsies of metastases and serum collected at time points during treatment.

      EXPLORATORY OBJECTIVES:

      I. To evaluate potential biomarkers of immune response to combined immune-checkpoint
      inhibition with SABR and correlate this with clinical response to treatment.

      II. To evaluate potential biomarkers of immune response including cervical and rectal
      microbial diversity, cervical immune cell infiltration and peripheral immune cell activation
      as correlates of clinical response to treatment.

      OUTLINE:

      Participants receive tremelimumab intravenously (IV) over 1 hour followed by durvalumab IV
      over 1 hour on day 1 of each cycle. Participants also undergo SABR over 30-45 minutes on days
      8, 10, and 12 of cycle 1. Treatment with tremelimumab repeats every 4 weeks for up to 4
      cycles, and treatment with durvalumab repeats every 4 weeks for up to 8 cycles in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up at 30 days, at 2, 3, 4, 6,
      8, 10, and 12 months, and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tremelimumab, durvalumab, SABR)ExperimentalParticipants receive tremelimumab IV over 1 hour followed by durvalumab IV over 1 hour on day 1 of each cycle. Participants also undergo SABR over 30-45 minutes on days 8, 10, and 12 of cycle 1. Treatment with tremelimumab repeats every 4 weeks for up to 4 cycles, and treatment with durvalumab repeats every 4 weeks for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent obtained from subject prior to any protocol related
             procedures

          -  Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.

          -  Body weight > 30 kg

          -  Must have an average life expectancy of 6 months

          -  Patient is able and willing to comply with protocol and study procedures for the
             duration of the study including undergoing treatment and scheduled visits and
             examinations including follow-up visits

          -  Histological diagnosis of recurrent or metastatic cervical, vaginal, or vulvar cancer
             or an unknown pelvic malignancy most likely to have arisen from these sites as
             determined clinically by the treating physicians (i.e. squamous cell carcinoma or
             adenocarcinoma that is high risk [HR] human papillomavirus positive [HPV]+, but not
             limited to this example).

          -  Metastatic disease in at least two distinct lesions (including the index lesion to be
             treated) with at least one site outside of the radiation field and evaluable by
             Response Evaluation Criteria in Solid Tumors (RECIST) criteria for evaluation of
             response

          -  At least one index lesion to be treated measuring 1 cm amenable to hypofractionated
             radiation therapy

          -  Staging computed tomography (CT) scans done prior to enrollment

          -  Have had at least one line of prior platinum-based systemic chemotherapy once
             diagnosed with recurrence or metastatic disease if primary cervical cancer. If a
             patient has primary vulvar or vaginal cancer, there is not a requirement.

          -  May have received 1 prior biologic regimen (i.e. avastin) but not within 4 weeks of
             enrollment

          -  Full recovery from the acute effects of prior treatments, defined as effects having
             resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
             Events (CTCAE) version (v) 4.03 grade 0 or 1 with the exception of alopecia and
             certain laboratory values as outlined below; subjects with irreversible toxicity that
             is not reasonably expected to be exacerbated by durvalumab and tremelimumab may be
             included (e.g., hearing loss, neuropathy) upon approval of the principal investigator
             (PI)

          -  In patients with central nervous system (CNS) metastases, metastases must be
             asymptomatic at the time of day 1 of the study and meet the following criteria:

               -  Brain metastases should have been treated with either whole brain radiation
                  therapy (WBRT), stereotactic radiosurgery (SRS)/gamma-knife, or surgical
                  resection;

               -  At least 28 days without progression of CNS metastases as evidenced by magnetic
                  resonance imaging (MRI) or CT from last day of treatment with radiation to the
                  CNS metastases;

               -  At least 3 months from surgical resection (if had surgery) with stability on MRI
                  brain at enrollment;

               -  At least 14 days since last dose of corticosteroids;

               -  Must not have leptomeningeal disease or cord compression

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
             limit of normal (ULN); for subjects with liver metastasis, ALT and AST =< 5 x ULN
             within 3 weeks prior to initial treatment

          -  Total bilirubin =< 1.5 x ULN except in patients with documented Gilbert's syndrome or
             liver metastasis, who must have a baseline total bilirubin 3.0 mg/dl within 3 weeks
             prior to initial treatment

          -  Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by
             24-hour urine collection for determination of creatinine clearance within 3 weeks
             prior to initial treatment

          -  Negative screening test results for hepatitis B, hepatitis C, and human
             immunodeficiency virus

          -  Absolute neutrophil count (ANC) >= 1,500 cells/ul without growth factor support prior
             to initial treatment

          -  Hemoglobin >= 9 g/dL prior to initial treatment

          -  Platelet count >= 100,000 platelets/ul prior to initial treatment

          -  Subjects must either be of non-reproductive potential (ie, post-menopausal by history;
             OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
             bilateral oophorectomy) or must have a negative serum or urine pregnancy test upon
             study entry; women will be considered post-menopausal if they have been amenorrheic
             for 12 months without an alternative medical cause; the following age-specific
             requirements apply:

               -  Women < 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy)

               -  Women >= 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses > 1 year ago, had
                  chemotherapy-induced menopause with last menses > 1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy)

          -  Females of childbearing potential who are sexually active with a nonsterilized male
             partner must use highly effective method of contraception from the time of screening,
             and must agree to continue using such precautions for 180 days after the final dose of
             durvalumab and tremelimumab; cessation of contraception after this point should be
             discussed with a responsible physician; they must also refrain from egg cell donation
             for 180 days after the final dose of durvalumab and tremelimumab

               -  Note: A highly effective method of contraception is defined as one that results
                  in a low failure rate (i.e., less than 1% per year) when used consistently and
                  correctly; the acceptable methods of contraception include barrier methods (male
                  condom plus spermicide, copper T intrauterine device, levonorgesterel-releasing
                  intrauterine system) or hormonal methods (implants, hormone shot or injection,
                  combined pill, minipill, patch)

        Exclusion Criteria:

          -  Involvement in the planning and/or conduct of the study

          -  Previous enrollment in the present study

          -  Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of durvalumab monotherapy or 180 days after
             the last dose of durvalumab + tremelimumab combination therapy

          -  Prior treatment with an anti-CTLA-4, including tremelimumab PD-1 or PD-L1 inhibitor,
             including durvalumab

          -  Prior oncology vaccine therapy

          -  Prior radiation treatment to the index lesion to be treated

          -  Prior radiation which overlaps and precludes hypofractionated treatment to the index
             lesion

          -  Treatment with other investigational agent within 4 weeks to the first dose of
             tremelimumab or durvalumab

          -  Concomitant therapy with any of the following: interleukin-2 (IL-2), interferon, or
             other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive
             agents; other investigational therapies; all such therapies must have been
             discontinued > 4 weeks

          -  Any unresolved toxicity (CTCAE grade < 2) from previous anti-cancer therapy; (subjects
             with irreversible toxicity that is not reasonably expected to be exacerbated by the
             investigational product may be included (e.g., hearing loss, peripherally neuropathy)

          -  Any prior grade >= 3 immune-related adverse event (imAE) while receiving any previous
             immunotherapy agent, or any unresolved imAE > grade 1

          -  Treatment with a vascular endothelial growth factor (VEGF) inhibitor within the last 6
             weeks

          -  Major surgical procedure (as defined by the treating physician) within 28 days prior
             to the first dose of durvalumab and tremelimumab or still recovering from prior
             surgery

          -  Active cardiac disease defined as unstable angina, uncontrolled hypertension,
             myocardial infarction in the last six months (unless successfully treated with
             coronary artery bypass grafting [CABG] or percutaneous transluminal coronary
             angioplasty [PTCA]), uncontrolled arrhythmia, or symptomatic congestive heart failure;
             > 3 heart-related hospitalizations in the past year

          -  Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3
             electrocardiogram (ECGs) using Fridericia's correction

          -  Severe chronic obstructive pulmonary disease (COPD) requiring > 3 hospitalizations in
             the past year

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
             exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or
             Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]); the following are exceptions to this
             criterion:

               -  Patients with vitiligo or alopecia;

               -  Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
                  replacement;

               -  Any chronic skin condition that does not require systemic therapy;

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician;

               -  Patients with celiac disease controlled by diet alone

          -  Active or prior documented interstitial lung disease

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab and tremelimumab with the exceptions of intranasal and inhaled
             corticosteroids, systemic corticosteroids at physiologic doses not to exceed 10 mg/day
             of prednisone or equivalent, or steroids used transiently to control contrast agent
             allergies for radiographic studies

          -  History of allogeneic organ transplant

          -  History of hypersensitivity to durvalumab or tremelimumab or any CTLA4, PD1, or PDL-1
             inhibitor

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving durvalumab or tremelimumab

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis (TB) testing
             in line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
             surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus
             (positive HIV 1/2 antibodies); patients with a past or resolved HBV infection (defined
             as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are
             eligible; patients positive for hepatitis C virus (HCV) antibody are eligible only if
             polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

          -  History of prior bowel fistula, ulcerations, or perforations

          -  Evidence of progressive or symptomatic central nervous system (CNS) metastases or
             leptomeningeal disease

          -  Uncontrolled inter-current illness, including, but not limited to, ongoing or active
             infection requiring systemic treatment, current or history of prior radiation induced
             pneumonitis, interstitial lung disease, or psychiatric illness/social situations that
             would limit compliance with study requirement or compromise the ability of the subject
             to give written informed consent

          -  Other active invasive malignancy; history of non-invasive malignancies such as ductal
             carcinoma in situ of the breast, non-melanomatous carcinoma of the skin, is allowed,
             as is history of other invasive malignancy that is in remission for >= 5 years after
             treatment with curative intent

          -  Any medical, psychological, or social condition that, in the opinion of the treating
             physician would interfere with evaluation of the investigational product or
             interpretation of subject safety or study results
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03
Time Frame:Up to 3 months after last dose of durvalumab
Safety Issue:
Description:Will be assessed based on dose limiting toxicities (DLTs) and based on adverse events (AEs) throughout the entire treatment period. In the overall assessment of adverse events, AEs will be tabulated by body system, type and grade, overall and by disease cohort. The number and percentage of patients experiencing at least one grade 3 or higher AE will also be reported.

Secondary Outcome Measures

Measure:Response to treatment by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related response criteria
Time Frame:Up to 1 year
Safety Issue:
Description:This will be measured in both treated and untreated lesions with computed tomography (CT) imaging or other appropriate imaging modalities. Immune-related response is reported as number and percent of patients with two-sided 80% confidence intervals (CI). Because each patient will have multiple lesions, a generalized linear mixed model will be used, if possible, to calculate overall response, as well as response by index or non-index lesion. The depth and duration of response will be depicted using waterfall and swimmer plots.
Measure:Progression-Free Survival
Time Frame:From the start of therapy up to first documented disease progression or death from any cause, assessed up to 1 year
Safety Issue:
Description:To summarize progression free survival we will use Kaplan Meier analysis, reporting the median with confidence interval.
Measure:Overall Survival
Time Frame:From start of therapy to death from any cause, assessed up to 1 year
Safety Issue:
Description:To summarize overall survival we will use Kaplan Meier analysis, reporting the median with confidence interval.
Measure:Time to next treatment (TTNT)
Time Frame:From the end of immune-checkpoint inhibition treatment to institution of next therapy, assessed up to 1 year
Safety Issue:
Description:To summarize time to next treatment we will use Kaplan Meier analysis, reporting the median with confidence interval.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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