Clinical Trials /

Brachytherapy With Durvalumab or Tremelimumab for the Treatment of Patients With Platinum-Resistant, Refractory, Recurrent, or Metastatic Gynecological Malignancies

NCT04395079

Description:

This phase II trial studies the side effects and how well brachytherapy with durvalumab or tremelimumab work for the treatment of gynecological malignancies that is resistant to platinum therapy (platinum-resistant), does not respond to treatment (refractory), has come back (recurrent), or has spread to other places in body (metastatic). Brachytherapy, also known as internal radiation therapy, uses radioactive material placed directly into or near a tumor to kill tumor cells. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial is being done to see whether brachytherapy with durvalumab or tremelimumab works better in treating patients with gynecological malignancies.

Related Conditions:
  • Malignant Female Reproductive System Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Brachytherapy With Durvalumab or Tremelimumab for the Treatment of Patients With Platinum-Resistant, Refractory, Recurrent, or Metastatic Gynecological Malignancies
  • Official Title: Brachytherapy With Durvalumab (MEDI4736) and Tremelimumab in Subjects With Platinum-Resistant or Refractory and Recurrent or Metastatic Gynecological Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 19-000459
  • SECONDARY ID: NCI-2020-01095
  • SECONDARY ID: 19-000459
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT04395079

Conditions

  • Metastatic Malignant Female Reproductive System Neoplasm
  • Platinum-Resistant Malignant Female Reproductive System Neoplasm
  • Recurrent Malignant Female Reproductive System Neoplasm
  • Refractory Malignant Female Reproductive System Neoplasm

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, MEDI4736Arm I (durvalumab, brachytherapy)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabArm II (tremelimumab, brachytherapy)

Purpose

This phase II trial studies the side effects and how well brachytherapy with durvalumab or tremelimumab work for the treatment of gynecological malignancies that is resistant to platinum therapy (platinum-resistant), does not respond to treatment (refractory), has come back (recurrent), or has spread to other places in body (metastatic). Brachytherapy, also known as internal radiation therapy, uses radioactive material placed directly into or near a tumor to kill tumor cells. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial is being done to see whether brachytherapy with durvalumab or tremelimumab works better in treating patients with gynecological malignancies.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety of the treatment combination consisting of brachytherapy and
      tremelimumab. (Safety lead-in) II. To determine the median progression-free survival with
      brachytherapy and checkpoint inhibition with either durvalumab or tremelimumab. (Dose
      expansion)

      SECONDARY OBJECTIVES:

      I. To estimate the efficacy of brachytherapy and durvalumab or brachytherapy and tremelimumab
      in terms of:

      Ia. Local control of the irradiated tumor. Ib. Overall response rate. Ic. Response at
      non-irradiated lesions in subjects with multiple sites of disease subjects.

      Id. Duration of response. Ie. Disease specific survival. If. Overall survival. II. To further
      determine the safety and tolerability of brachytherapy with durvalumab and brachytherapy with
      tremelimumab (expansion cohorts).

      EXPLORATORY OBJECTIVE:

      I. To explore the immunologic changes associated with the combination of brachytherapy with
      durvalumab and brachytherapy with tremelimumab.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive durvalumab intravenously (IV) on day 1. Treatment repeats every 28
      days for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients
      then undergo brachytherapy on day 8. Treatment repeats every 21 days for 3 fractions in the
      absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive tremelimumab IV on day 1. Treatment repeats every 28 days for 2-4
      cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo
      brachytherapy on day 8. Treatment repeats every 21 days for 3 fractions in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 12 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (durvalumab, brachytherapy)ExperimentalPatients receive durvalumab IV on day 1. Treatment repeats every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo brachytherapy on day 8. Treatment repeats every 21 days for 3 fractions in the absence of disease progression or unacceptable toxicity.
  • Durvalumab
Arm II (tremelimumab, brachytherapy)ExperimentalPatients receive tremelimumab IV on day 1. Treatment repeats every 28 days for 2-4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo brachytherapy on day 8. Treatment repeats every 21 days for 3 fractions in the absence of disease progression or unacceptable toxicity.
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects with platinum-resistant or refractory, recurrent or metastatic gynecological
             malignancies, including ovarian, endometrial, or cervical cancer are eligible for
             enrollment. Subjects unsuitable or refusing platinum-based chemotherapy are allowed to
             enrolled

          -  Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
             version (v)1.1 criteria. Thus, subjects with metastatic disease must have at least 1
             lesion, not previously irradiated, that can be accurately measured at baseline as >=10
             mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm)
             with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable
             for accurate repeated measurement as per RECIST v1.1 guidelines

          -  Disease amenable to be treated safely with brachytherapy

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Life expectancy of >= 12 weeks

          -  Subjects must consent to provide an archived tumor specimen from within 12 months
             prior to study entry (ie, from subject signing consent to participate in the study).
             If not available, subjects should have at least 1 lesion amenable to biopsy and
             consent to provide a pre-treatment fresh biopsy. Additional archival tissue from
             beyond 12 months prior to study entry is also requested, if available, to support
             exploratory analyses

          -  Hemoglobin >= 9.0 g/dL

          -  Absolute neutrophil count (ANC) >= 1.5 (or 1.0) x (>= 1500 per mm^3)

          -  Platelet count >= 100 (or 75) x 10^9/L (>= 75,000 per mm^3)

          -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)

               -  This will not apply to subjects with confirmed Gilbert's syndrome (persistent or
                  recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
                  hemolysis or hepatic pathology), who will be allowed only in consultation with
                  their physician

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal unless liver metastases are present, in
             which case it must be =< 5 x ULN

          -  Creatinine < 3 x upper limit of normal

          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal subjects. 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)

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

        Exclusion Criteria:

          -  Prior use of checkpoint inhibitors

          -  Prior radiation in which the 50% isodose line overlaps with intended site for
             brachytherapy

          -  Radiation treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks of the first dose of study drug

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site)

          -  Participation in another clinical study with an investigational therapeutic
             pharmaceutical agent i.e. chemotherapy, targeted therapy, or immunotherapy =< 21 days
             or =< 5 half-lives

          -  Concurrent enrolment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study

          -  Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
             therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies) =< 21 days or 5 half-lives prior to the first dose of study drug. If
             sufficient wash-out time has not occurred due to the schedule or pharmacokinetics (PK)
             properties of an agent, a longer wash-out period will be required, as agreed by
             AstraZeneca/MedImmune and the investigator

          -  Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria
             for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria

          -  Subjects with grade >= 2 neuropathy will be evaluated on a case-by-case basis after
             consultation with the study physician

          -  Subjects with irreversible toxicity not reasonably expected to be exacerbated by
             treatment with durvalumab or tremelimumab may be included only after consultation with
             the study physician

          -  Any concurrent chemotherapy, investigation product (IP), biologic, or hormonal therapy
             for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
             conditions (e.g., hormone replacement therapy) is acceptable

          -  Major surgical procedure (as defined by the investigator) within 28 days prior to the
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
             acceptable

          -  History of allogenic organ transplantation

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., 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:

               -  Subjects with vitiligo or alopecia

               -  Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

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

               -  Subjects with celiac disease controlled by diet alone

          -  Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring adverse events (AEs) or compromise the ability of the subject to
             give written informed consent

          -  History of another primary malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease >= 5
                  years before the first dose of IP and of low potential risk for recurrence

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated carcinoma in situ without evidence of disease

          -  History of leptomeningeal carcinomatosis

          -  Brain metastases or spinal cord compression. Subjects with suspected brain metastases
             at screening should have an MRI (preferred) or CT each preferably with IV contrast of
             the brain prior to study entry. Brain metastases will not be recorded as RECIST target
             lesions at baseline if study allows subjects with brain metastasis (mets)

          -  Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
             identified either on the baseline brain imaging (RECIST) obtained during the screening
             period or identified prior to signing the ICF. Subjects whose brain metastases have
             been treated may participate provided they show radiographic stability (defined as 2
             brain images, both of which are obtained after treatment to the brain metastases.
             These imaging scans should both be obtained at least four weeks apart and show no
             evidence of intracranial progression). In addition, any neurologic symptoms that
             developed either as a result of the brain metastases or their treatment must have
             resolved or be stable either, without the use of steroids, or are stable on a steroid
             dose of =< 10 mg/day of prednisone or its equivalent for at least 14 days prior to the
             start of treatment. Brain metastases will not be recorded as RECIST target lesions at
             baseline

          -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms
             calculated from 3 electrocardiogram (ECG)s (within 15 minutes at 5 minutes apart)

               -  For durvalumab monotherapy and durvalumab + tremelimumab combination studies this
                  criterion can be removed. For durvalumab +/- tremelimumab in combination with an
                  agent with pro-arrhythmic potential or where effect of the combination on QT is
                  not known if this criterion should be retained. Subject safety and the cardiac
                  SKG should be consulted as needed

          -  History of active primary immunodeficiency

          -  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). Subjects with a past or resolved HBV infection (defined
             as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are
             eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if
             polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
             Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to
             30 days after the last dose of IP

          -  Female subjects who are pregnant or breastfeeding or male or female subjects of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of durvalumab monotherapy or180 days after
             the last dose of durvalumab + tremelimumab combination therapy

          -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients

          -  Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
             study regardless of treatment arm assignment

          -  Determined by the investigator that the subject is unsuitable to participate in the
             study and the subject is unlikely to comply with study procedures, restrictions and
             requirements

          -  Known allergy or hypersensitivity to IP or any excipient
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events (safety lead-in)
Time Frame:Up to 90 days
Safety Issue:
Description:Toxicity will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0 criteria.

Secondary Outcome Measures

Measure:Local control at the irradiated site
Time Frame:Up to 2 years
Safety Issue:
Description:Will be determined by RECIST v 1.1 from the date of randomization to the date of first local progression.
Measure:Overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:ORR will be as determined by RECIST v 1.1. The ORR will be defined as the number (%) of subjects with at least 1 visit response of complete response (CR) or partial response (PR). Data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR. Subjects who go off treatment without progression receive a subsequent therapy, and then responds will not be included as responders in the ORR. The overall response rate will also be compared between treatment groups.
Measure:Response at non-irradiated lesions in subjects with multiple sites of disease
Time Frame:Up to 2 years
Safety Issue:
Description:As determined by RECIST v 1.1 with response (PR and CR) sites away from the primary irradiated tumor.
Measure:Duration of response (DoR)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be defined as the time from the date of the first documented response until the first date of documented progression or death. The end of response should coincide with the date of progression or death from any cause used for the RECIST 1.1 PFS endpoint. The time of initial response will be defined as the latest of dates contributing towards the first visit response of CR or PR. If a subject does not progress following a response, then their DoR will be censored at the PFS censoring time. DoR will not be defined for those subjects who do not have a documented response.
Measure:Disease-specific survival
Time Frame:From the first day of treatment to the date of death related to treatment and/or disease, assessed up to 2 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:From the first day of treatment to the date of death due to any cause as determined, assessed up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

May 14, 2020