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Durvalumab, Tremelimumab + Radiotherapy in Gynecologic Cancer

Primary Purpose

Recurrent Gynecological Cancer, Metastatic Cervical Cancer, Metastatic Ovarian Cancer

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Durvalumab
Tremelimumab
Radiation Therapy
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Gynecological Cancer focused on measuring Recurrent gynecological cancer, Metastatic Cervical Cancer, Metastatic Ovarian Cancer, Metastatic Vaginal Cancer, Metastatic Vulvar Cancer, Metastatic Endometrial Cancer, Recurrent Cervical Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Vaginal Cancer, Recurrent Vulvar Cancer, Recurrent Endometrial Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Ability to understand and the willingness to sign a written informed consent document. 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.
  • Participants must have histologically or cytologically confirmed endometrial, ovarian (including ovarian epithelial, fallopian tube, primary peritoneal), cervical, vaginal, or vulvar cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
  • Participants must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥20 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease. See also 3.1.10 as all measurable/target lesions must not be located within the planned radiation field for the expansion cohort.
  • Patients must have progressive disease following prior therapy. Specifically, patients must have progressed on platinum-based chemotherapy.
  • At least 21 days must have elapsed from prior therapy (chemotherapy or radiation).
  • Age of 18 years or older. Because no dosing or adverse event data are currently available on the use of durvalumab in combination with tremelimumab and radiation in patients <18 years of age, children are excluded from this study.
  • ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A).
  • Body weight of greater than 30 kg.
  • Participants must have normal organ and marrow function as defined below:

    • Hgb >=9g/dl
    • Absolute neutrophil count ≥1,500/mcL
    • Platelets ≥100,000/mcL
    • Total bilirubin <=1.5 x normal institutional limits.

      --- This last criterion will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician.

    • AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal
    • Creatinine within normal institutional limits

      --- OR

    • Creatinine clearance >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
    • Males:

      • Creatinine CL (mL/min) = Weight (kg) x (140 - Age)
      • 72 x serum creatinine (mg/dL)
    • Females:

      • Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85
      • 72 x serum creatinine (mg/dL)
  • Patients must have at least one lesion not previously irradiated (and not within a previously irradiated field) for which palliative radiation to the abdomen and/or pelvis is potentially indicated and could be safely delivered at the radiation doses specified in this protocol. This lesion must not be within the CNS (brain or spinal cord), bone or liver, and must not require urgent or emergent palliative radiation given the timing of radiation specified on this protocol. Furthermore, this lesion must be located in the abdomen or pelvis and measure at least 2 cm (minimum dimension) and no greater than 6 cm (maximum dimension). Palliative radiotherapy would entail involved-field radiotherapy to a single lesion or region to encompass gross disease; whole-abdomen radiotherapy would not be permitted. Patients who received prior vaginal brachytherapy would be permitted to receive palliative pelvic radiation. In the expansion cohort at the MTD, this lesion must not be the only measurable lesion (as defined in 3.1.3) so that it is possible to determine the response rate outside of the radiation treatment field.
  • The effects of durvalumab and tremelimumab on the developing human fetus are unknown. For this reason and because radiation is known to be teratogenic, evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-menopausal patients is required. 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 oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1-year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
    • Women of child-bearing potential who are sexually active with a non-sterilized male partner must agree to use at least 1 method of highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 180 days after the last dose of therapy. Highly effective methods of contraception, defined as those that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, are described in section 5.5. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

Exclusion Criteria

  • Prior exposure to immune-mediated therapy, including anti-PD-1, anti-PD-L1 (including durvalumab) or anti-CTLA-4 directed therapy (including tremelimumab). Therapeutic anticancer vaccines are not included in this category. Exposure to other investigational agents may be permitted after discussion with the Study PI.
  • Chemotherapy, targeted therapy, biologic or hormonal agents within 3 weeks prior to entering the study.
  • Radiation therapy within 3 weeks prior to entering the study.
  • Current receipt of any other investigational agents.
  • Any unresolved toxicity of NCI CTCAE Grade ≥2, including electrolyte abnormalities, from previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.

    • Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
    • Patients 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.
  • Patients with untreated brain metastases, spinal cord compression, or leptomeningeal carcinomatosis are excluded from this clinical trial because of their poor prognosis, because of symptoms that may arise from inflammatory reactions, and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastases or spinal cord compression previously treated with radiation and/or surgery are allowed if local treatment was >30 days ago, most recent MRI demonstrates stability or decrease in size of all lesions, and the patient has no current neurologic symptoms related to the metastases and treatment and no requirement for corticosteroids related to the prior treatment.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to tremelimumab and durvalumab or previous toxicity attributed to durvalumab or other PD-1 or PD-L1 directed therapy that led to drug discontinuation.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, interstitial lung disease, pneumonitis, active peptic ulcer disease or gastritis, active bleeding diatheses, or serious chronic gastrointestinal conditions associated with diarrhea.
  • Pregnant women are excluded from this study because durvalumab and tremelimumab are immune checkpoint inhibitors with the potential for teratogenic or abortifacient effects, as is radiation therapy.
  • A nursing mother unwilling to discontinue breastfeeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with durvalumab, tremelimumab and radiation, breastfeeding should be discontinued if the mother is treated with durvalumab, tremelimumab and radiation.
  • Female patients who are pregnant or breastfeeding or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period
  • HIV-positive patients are ineligible due to the risks associated with immune checkpoint blockade.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab and 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 pre-medication for hypersensitivity reactions (e.g., CT scan pre-medication)
  • Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of immunotherapy. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • History of allogeneic organ transplantation
  • Active or prior documented autoimmune or inflammatory disorders. Patients without active disease in the last 5 years may be included after consultation with the study physician. This includes: inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, and diverticulitis with the exception of diverticulosis; sarcoidosis syndrome, or other serious GI chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome (granulomatosis with polyangiitis); myasthenia gravis; Graves' disease; rheumatoid arthritis; hypophysitis; or uveitis. The following are exceptions to this criterion:

    • Vitiligo or alopecia
    • Hypothyroidism (e,g,, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
    • Any chronic skin condition that does not require systemic therapy
    • Celiac disease controlled by diet alone
  • 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 study drug 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 (e.g., cervical cancer in situ)
  • Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 consecutive electrocardiograms (EKGs) using Fridericia's Correction at baseline or before dosing. Thereafter, only 1 EKG is required during visits unless an abnormality is found and in which case, confirmation by triplicate EKGs will be needed.
  • History of active primary immunodeficiency
  • Known history of previous clinical diagnosis of tuberculosis
  • Active infection including hepatitis B (known positive HBV surface antigen [HBsAg] result) or hepatitis C. 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 (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational treatment. Note: patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of investigational treatment.
  • Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Any condition that, in the opinion of the Investigator, would interfere with evaluation of the investigational treatment or interpretation of patient safety or study results.

Sites / Locations

  • Martin King

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Phase I Safety Lead-In

Phase I Radiation Dose Evaluation

Arm Description

A modified 3+3 design will be used in this trial Lead-in phase with Durvalumab* and radiation therapy *q4 weeks durvalumab for 13 cycles or until progression

Durvalumab Tremelimumab* -- Start radiation dose from safety lead-in (level 0 or level -1) *q4 weeks durvalumab / tremelimumab for 4 cycles and continue durvalumab for 13 cycles or until disease progression

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of Radiotherapy with durvalumab and tremelimumab
Incidence of dose-limiting toxicities for each dose level or regimen

Secondary Outcome Measures

Overall Response Rate
RECIST and immune RECIST (irRC) criteria
Local Response Rate
Response rate within the radiation field by RECIST and irRC criteria
Local Control Rate
Tumor control within the radiation field by RECIST and irRC criteria
Abscopal Response Rate
Abscopal response rate for measurable disease outside the radiation field by RECIST and irRC criteria
Response Duration
Time from overall response by RECIST or irRC until time of recurrent or progressive disease
Progression Free Survival Rate
From start of treatment to time of progression or death
Overall Survival Rate
From start of treatment until death due to any cause

Full Information

First Posted
September 7, 2017
Last Updated
July 31, 2023
Sponsor
Dana-Farber Cancer Institute
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT03277482
Brief Title
Durvalumab, Tremelimumab + Radiotherapy in Gynecologic Cancer
Official Title
A Phase 1 Study of Durvalumab, Tremelimumab and Radiotherapy in Recurrent Gynecologic Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Terminated
Why Stopped
Expansion cohort was not open
Study Start Date
June 1, 2018 (Actual)
Primary Completion Date
July 15, 2022 (Actual)
Study Completion Date
July 15, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This research study is evaluating the safety and effectiveness of 2 immunotherapy drugs in combination with radiation therapy as a possible treatment for recurrent or metastatic gynecologic cancer. The names of the immunotherapy drugs involved in this study are: Durvalumab Tremelimumab
Detailed Description
This research study is a Phase I clinical trial, which tests the safety of an investigational drug or drugs and also tries to define the appropriate dose and combination of the investigational drugs to use for further studies. "Investigational" means that the drugs are being studied but have not been approved by the FDA (the U.S. Food and Drug Administration). In this study, the combination of durvalumab and tremelimumab is considered to be investigational and as such has not been approved for this or any cancer. -- Durvalumab and tremelimumab are immunotherapy drugs that may stop cancer cells from growing by activating the immune system. The immune system is one of the body's natural defenses against the growth of cancer cells. AstraZeneca has evaluated the effectiveness and side effects of both durvalumab and tremelimumab individually for many cancer types, including lung, head and neck cancer, and melanoma. These types of immunotherapy drugs are also being studied in ovarian, endometrial and cervical cancer. In addition, AstraZeneca has studied the combination of durvalumab and tremelimumab in participants with lung and pancreatic cancers. Based on these studies, AstraZeneca has determined the dosing, schedule and expected side effects for the 2 study drugs when delivered together. In women with recurrent or metastatic gynecologic cancer, radiation therapy is often used to help with symptoms, such as bleeding, pain or swelling. Clinical reports have shown that radiation treatment can increase the body's response to an immunotherapy drug against tumors both within and outside the radiation field. This study is the first in which the combination of durvalumab, tremelimumab and abdominal or pelvic radiation is given to humans. The investigators hope that this combination with radiation will lead to a better treatment response to the immunotherapy drugs. The investigators will also look to see if participants whose tumors contain a particular genetic make-up have a better response to immunotherapy and radiation treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Gynecological Cancer, Metastatic Cervical Cancer, Metastatic Ovarian Cancer, Metastatic Vaginal Cancer, Metastatic Vulvar Cancer, Metastatic Endometrial Cancer, Recurrent Cervical Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Vaginal Cancer, Recurrent Vulvar Cancer, Recurrent Endometrial Cancer
Keywords
Recurrent gynecological cancer, Metastatic Cervical Cancer, Metastatic Ovarian Cancer, Metastatic Vaginal Cancer, Metastatic Vulvar Cancer, Metastatic Endometrial Cancer, Recurrent Cervical Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Vaginal Cancer, Recurrent Vulvar Cancer, Recurrent Endometrial Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase I Safety Lead-In
Arm Type
Experimental
Arm Description
A modified 3+3 design will be used in this trial Lead-in phase with Durvalumab* and radiation therapy *q4 weeks durvalumab for 13 cycles or until progression
Arm Title
Phase I Radiation Dose Evaluation
Arm Type
Experimental
Arm Description
Durvalumab Tremelimumab* -- Start radiation dose from safety lead-in (level 0 or level -1) *q4 weeks durvalumab / tremelimumab for 4 cycles and continue durvalumab for 13 cycles or until disease progression
Intervention Type
Drug
Intervention Name(s)
Durvalumab
Other Intervention Name(s)
Imfinizi, MEDI4736
Intervention Description
Durvalumab is given by intravenous infusion every 4 weeks for a maximum of 13 doses over 52 weeks. One cycle is defined as every 4 weeks. Each infusion will take approximately 1 hour.
Intervention Type
Drug
Intervention Name(s)
Tremelimumab
Other Intervention Name(s)
CP-675,206, CP-675
Intervention Description
Tremelimumab is given by intravenous infusion every 4 weeks for a maximum of 4 doses over 16 weeks. One cycle is defined as every 4 weeks. If receiving both durvalumab and tremelimumab for the first 4 cycles, they will be given on the same day. Each infusion will take approximately 1 hour
Intervention Type
Radiation
Intervention Name(s)
Radiation Therapy
Intervention Description
Radiation treatment will begin on the same day as the first immunotherapy infusion or on the following day. The radiation treatment course is either 1 day or 5 days.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) of Radiotherapy with durvalumab and tremelimumab
Description
Incidence of dose-limiting toxicities for each dose level or regimen
Time Frame
8 Weeks
Secondary Outcome Measure Information:
Title
Overall Response Rate
Description
RECIST and immune RECIST (irRC) criteria
Time Frame
One Year
Title
Local Response Rate
Description
Response rate within the radiation field by RECIST and irRC criteria
Time Frame
One Year
Title
Local Control Rate
Description
Tumor control within the radiation field by RECIST and irRC criteria
Time Frame
Baseline to 6 months, 12 Months
Title
Abscopal Response Rate
Description
Abscopal response rate for measurable disease outside the radiation field by RECIST and irRC criteria
Time Frame
One Year
Title
Response Duration
Description
Time from overall response by RECIST or irRC until time of recurrent or progressive disease
Time Frame
One Year
Title
Progression Free Survival Rate
Description
From start of treatment to time of progression or death
Time Frame
Baseline to 6 months, 12 Months
Title
Overall Survival Rate
Description
From start of treatment until death due to any cause
Time Frame
Baseline to 6 months, 12 Months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Ability to understand and the willingness to sign a written informed consent document. 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. Participants must have histologically or cytologically confirmed endometrial, ovarian (including ovarian epithelial, fallopian tube, primary peritoneal), cervical, vaginal, or vulvar cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. Participants must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥20 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease. See also 3.1.10 as all measurable/target lesions must not be located within the planned radiation field for the expansion cohort. Patients must have progressive disease following prior therapy. Specifically, patients must have progressed on platinum-based chemotherapy. At least 21 days must have elapsed from prior therapy (chemotherapy or radiation). Age of 18 years or older. Because no dosing or adverse event data are currently available on the use of durvalumab in combination with tremelimumab and radiation in patients <18 years of age, children are excluded from this study. ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A). Body weight of greater than 30 kg. Participants must have normal organ and marrow function as defined below: Hgb >=9g/dl Absolute neutrophil count ≥1,500/mcL Platelets ≥100,000/mcL Total bilirubin <=1.5 x normal institutional limits. --- This last criterion will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician. AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal Creatinine within normal institutional limits --- OR Creatinine clearance >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) Patients must have at least one lesion not previously irradiated (and not within a previously irradiated field) for which palliative radiation to the abdomen and/or pelvis is potentially indicated and could be safely delivered at the radiation doses specified in this protocol. This lesion must not be within the CNS (brain or spinal cord), bone or liver, and must not require urgent or emergent palliative radiation given the timing of radiation specified on this protocol. Furthermore, this lesion must be located in the abdomen or pelvis and measure at least 2 cm (minimum dimension) and no greater than 6 cm (maximum dimension). Palliative radiotherapy would entail involved-field radiotherapy to a single lesion or region to encompass gross disease; whole-abdomen radiotherapy would not be permitted. Patients who received prior vaginal brachytherapy would be permitted to receive palliative pelvic radiation. In the expansion cohort at the MTD, this lesion must not be the only measurable lesion (as defined in 3.1.3) so that it is possible to determine the response rate outside of the radiation treatment field. The effects of durvalumab and tremelimumab on the developing human fetus are unknown. For this reason and because radiation is known to be teratogenic, evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-menopausal patients is required. 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 oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1-year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Women of child-bearing potential who are sexually active with a non-sterilized male partner must agree to use at least 1 method of highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 180 days after the last dose of therapy. Highly effective methods of contraception, defined as those that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, are described in section 5.5. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Exclusion Criteria Prior exposure to immune-mediated therapy, including anti-PD-1, anti-PD-L1 (including durvalumab) or anti-CTLA-4 directed therapy (including tremelimumab). Therapeutic anticancer vaccines are not included in this category. Exposure to other investigational agents may be permitted after discussion with the Study PI. Chemotherapy, targeted therapy, biologic or hormonal agents within 3 weeks prior to entering the study. Radiation therapy within 3 weeks prior to entering the study. Current receipt of any other investigational agents. Any unresolved toxicity of NCI CTCAE Grade ≥2, including electrolyte abnormalities, from previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Patients 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. Patients with untreated brain metastases, spinal cord compression, or leptomeningeal carcinomatosis are excluded from this clinical trial because of their poor prognosis, because of symptoms that may arise from inflammatory reactions, and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastases or spinal cord compression previously treated with radiation and/or surgery are allowed if local treatment was >30 days ago, most recent MRI demonstrates stability or decrease in size of all lesions, and the patient has no current neurologic symptoms related to the metastases and treatment and no requirement for corticosteroids related to the prior treatment. History of allergic reactions attributed to compounds of similar chemical or biologic composition to tremelimumab and durvalumab or previous toxicity attributed to durvalumab or other PD-1 or PD-L1 directed therapy that led to drug discontinuation. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, interstitial lung disease, pneumonitis, active peptic ulcer disease or gastritis, active bleeding diatheses, or serious chronic gastrointestinal conditions associated with diarrhea. Pregnant women are excluded from this study because durvalumab and tremelimumab are immune checkpoint inhibitors with the potential for teratogenic or abortifacient effects, as is radiation therapy. A nursing mother unwilling to discontinue breastfeeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with durvalumab, tremelimumab and radiation, breastfeeding should be discontinued if the mother is treated with durvalumab, tremelimumab and radiation. Female patients who are pregnant or breastfeeding or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period HIV-positive patients are ineligible due to the risks associated with immune checkpoint blockade. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab and 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 pre-medication for hypersensitivity reactions (e.g., CT scan pre-medication) Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of immunotherapy. Note: Local surgery of isolated lesions for palliative intent is acceptable. History of allogeneic organ transplantation Active or prior documented autoimmune or inflammatory disorders. Patients without active disease in the last 5 years may be included after consultation with the study physician. This includes: inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, and diverticulitis with the exception of diverticulosis; sarcoidosis syndrome, or other serious GI chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome (granulomatosis with polyangiitis); myasthenia gravis; Graves' disease; rheumatoid arthritis; hypophysitis; or uveitis. The following are exceptions to this criterion: Vitiligo or alopecia Hypothyroidism (e,g,, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment Any chronic skin condition that does not require systemic therapy Celiac disease controlled by diet alone 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 study drug 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 (e.g., cervical cancer in situ) Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 consecutive electrocardiograms (EKGs) using Fridericia's Correction at baseline or before dosing. Thereafter, only 1 EKG is required during visits unless an abnormality is found and in which case, confirmation by triplicate EKGs will be needed. History of active primary immunodeficiency Known history of previous clinical diagnosis of tuberculosis Active infection including hepatitis B (known positive HBV surface antigen [HBsAg] result) or hepatitis C. 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 (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational treatment. Note: patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of investigational treatment. Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent Any condition that, in the opinion of the Investigator, would interfere with evaluation of the investigational treatment or interpretation of patient safety or study results.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Martin King, MD, PhD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Martin King
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Durvalumab, Tremelimumab + Radiotherapy in Gynecologic Cancer

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