Stereotactic Ablative Radiotherapy (SABR) in Combination With Durvalumab and Tremelimumab in Patients With Cervical, Vaginal, or Vulvar Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03452332
Recruitment Status : Recruiting
First Posted : March 2, 2018
Last Update Posted : December 13, 2018
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to learn if it is safe to give a special type of radiation called stereotactic ablative radiotherapy (SABR) in combination with durvalumab and tremelimumab to patients with advanced forms of cervical, vaginal, or vulvar cancer that is recurrent (has returned after treatment) and/or metastatic (has spread). Researchers also want to learn if this combination can help to control the disease.

SABR is a type of radiation commonly used to treat various types of cancer with larger doses of radiation focused precisely at the tumor.

This is an investigational study. Durvalumab is FDA approved for the treatment of urothelial cancer. Tremelimumab is not FDA approved or commercially available. The use of these drugs in combination with SABR is investigational. SABR is delivered using FDA-approved and commercially available methods.

The study doctor can describe how the study drugs and radiation are designed to work.

Up to 18 patients will enroll in this multi-center study. Up to 9 will take part at MD Anderson.

Condition or disease Intervention/treatment Phase
Malignant Neoplasms of Female Genital Organs Cervical Cancer Vaginal Cancer Vulvar Cancer Drug: Durvalumab Drug: Tremelimumab Radiation: Stereotactic Ablative Radiotherapy (SABR) Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 18, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vulvar Cancer
Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Durvalumab + Tremelimumab + SABR

Participants receive Tremelimumab by vein over about 1 hour on Day 1 of Cycles 1-4. Participants receive Durvalumab by vein over about 1 hour on Day 1 of every cycle (about 1 hour after the end of the Tremelimumab dose during Cycles 1-4).

On Days 8, 10, and 12 of Cycle 1, participants also receive SABR over about 30-45 minutes each time.

Participants only receive SABR during cycle 1 and Tremelimumab over 4 cycles. Participants may continue to receive Durvalumab for up to 8 cycles.

Study conducted in 4 week cycles.

Drug: Durvalumab
Durvalumab 1500 mg by vein over about 1 hour on Day 1 of every cycle (about 1 hour after the end of the Tremelimumab dose during Cycles 1-4).
Other Name: MEDI4736

Drug: Tremelimumab
Tremelimumab 75 mg by vein given 1 week (+/- 3 days) prior to SABR then every 4 weeks for 4 cycles.
Other Names:
  • Ticilimumab
  • CP-675,206

Radiation: Stereotactic Ablative Radiotherapy (SABR)
SABR administered during cycle 1, day 7 +/- 3 days. SABR given in 3 fractions, every other day, to a total dose of 24 Gy (8 Gy per fraction x 3 fractions) completed within one week and targeted to the largest easily accessible metastases.
Other Name: Radiation therapy

Primary Outcome Measures :
  1. Safety Assessed Based on Dose Limiting Toxicities (DLTs) Based on Adverse Events (AEs) Assessed by NCI CTCAE v 4.03.) [ Time Frame: Baseline up to 8 months ]

Secondary Outcome Measures :
  1. Clinical Response Rate Measured by Tumor Response Based on RECIST Criteria v 1.1 [ Time Frame: Baseline up to 1 year ]
  2. Objective Response Defined as Complete Response (CR) or Partial Response (PR) by RECIST v1.1. [ Time Frame: Baseline up to 1 year ]
  3. Progression-Free Survival Defined as the Time From the Start of Therapy to First Documented Disease Progression or Death From Any Cause [ Time Frame: Baseline up to 1 year ]
  4. Overall Survival Defined as the Time From Start of Therapy to Death From any Cause. [ Time Frame: Baseline up to 1 year ]
  5. Time to Next Treatment (TTNT) Defined as the Time From the End of Immune-Checkpoint Inhibition Treatment on this Study to Institution of Next Therapy. [ Time Frame: Baseline up to 1 year ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Written informed consent obtained from subject prior to any protocol related procedures
  2. Adult female subjects (age 18 years or older) at time of study entry.
  3. Performance status ECOG 0-1
  4. Body weight >30 kg
  5. Must have an average life expectancy of 6 months.
  6. 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.
  7. Histological diagnosis of recurrent or metastatic cervical, vaginal, or vulvar cancer
  8. 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 RECIST criteria for evaluation of response.
  9. At least one index lesion to be treated measuring 1-7 cm amenable to hypofractionated radiation therapy.
  10. Staging CT scans done prior to enrollment.
  11. Have had at least one line of prior platinum-based systemic chemotherapy once diagnosed with recurrence or metastatic disease.
  12. May have received 1 prior biologic regimen (i.e. avastin) but not within 4 weeks of enrollment.
  13. Full recovery from the acute effects of prior treatments, defined as effects having resolved to NCI CTCAE v4.03 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 PI.
  14. 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: (a) Brain metastases should have been treated with either WBRT, SRS/Gamma-knife, or surgical resection; (b) At least 28 days without progression of CNS metastases as evidenced by magnetic resonance imaging (MRI) or computed tomography (CT) from last day of treatment with radiation to the CNS metastases; (c) At least 3 months from surgical resection (if had surgery) with stability on MRI brain at enrollment; (d) At least 14 days since last dose of corticosteroids; (e) Must not have leptomeningeal disease or cord compression
  15. Adequate hepatic and renal function documented within 3 weeks prior to initial treatment based on: (a) 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; (b) 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; (c) Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Females: CreatinineCL (mL/min) = [(Weight (kg) x (140-Age)) / (72 * serum creatinine (mg/dl)) ] * 0.85
  16. Negative screening test results for hepatitis B, hepatitis C, and human immunodeficiency virus
  17. Adequate hematological function documented prior to initial treatment based on: (a) Absolute neutrophil count (ANC) >/= 1,500 cells/ul without growth factor support; (b) Hemoglobin >/= 9 g/dL; (c) Platelet count >/= 100,000 platelets/ul
  18. 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:
  19. Continued: (a) 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); (b) 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).
  20. 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, Levonorgestrel-releasing intrauterine system) or hormonal methods (implants, hormone shot or injection, combined pill, minipill, patch).

Exclusion Criteria:

  1. Involvement in the planning and/or conduct of the study.
  2. Previous enrollment in the present study
  3. 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 or180 days after the last dose of durvalumab + tremelimumab combination therapy
  4. Received more than 2 prior systemic chemotherapy regimens, including adjuvant systemic chemotherapy following definitive chemoradiation (OUTBACK chemotherapy). Concurrent chemotherapy with prior radiation treatment is not to be counted
  5. Prior treatment with an anti-CTLA-4, including tremelimumab PD-1 or PD-L1 inhibitor, including durvalumab.
  6. Prior oncology vaccine therapy
  7. Prior radiation treatment to the index lesion to be treated.
  8. Prior radiation which overlaps and precludes hypofractionated treatment to the index lesion.
  9. Treatment with other investigational agent within 4 weeks to the first dose of Tremelimumab or Durvalumab
  10. Concomitant therapy with any of the following: IL-2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; all such therapies must have been discontinued > 4weeks.
  11. 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)
  12. Any prior Grade >/= 3 immune-related adverse event (imAE) while receiving any previous immunotherapy agent, or any unresolved imAE > Grade 1
  13. Treatment with a VEGF inhibitor within the last 6 weeks.
  14. 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
  15. Active cardiac disease defined as unstable angina, uncontrolled hypertension, myocardial infarction in the last six months (unless successfully treated with CABG or PTCA), uncontrolled arrhythmia, or symptomatic congestive heart failure; > 3 heart-related hospitalizations in the past year.
  16. Mean QT interval corrected for heart rate (QTc) >/= 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
  17. Severe COPD requiring > 3 hospitalizations in the past year
  18. 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: (a) Patients with vitiligo or alopecia; (b) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; (c) Any chronic skin condition that does not require systemic therapy; (d) Patients without active disease in the last 5 years may be included but only after consultation with the study physician; (e) Patients with celiac disease controlled by diet alone
  19. Active or prior documented interstitial lung disease
  20. 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.
  21. History of allogeneic organ transplant
  22. History of hypersensitivity to durvalumab or Tremelimumab or any CTLA4, PD1, or PDL-1 inhibitor.
  23. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
  24. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive 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 (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
  25. History of prior bowel fistula, ulcerations, or perforations.
  26. Evidence of progressive or symptomatic central nervous system (CNS) metastases or leptomeningeal disease.
  27. 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.
  28. 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.
  29. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03452332

Contact: Lilie L. Lin, MD 713-563-2300

United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Principal Investigator: Lilie L. Lin, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT03452332     History of Changes
Other Study ID Numbers: 2017-0548
NCI-2018-00627 ( Registry Identifier: NCI CTRP )
First Posted: March 2, 2018    Key Record Dates
Last Update Posted: December 13, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Malignant neoplasms of female genital organs
Cervical Cancer
Vaginal Cancer
Vulvar Cancer
Stereotactic Ablative Radiotherapy
Radiation therapy

Additional relevant MeSH terms:
Uterine Cervical Neoplasms
Vulvar Neoplasms
Vaginal Neoplasms
Genital Neoplasms, Female
Uterine Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Vulvar Diseases
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Vaginal Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents