BrUOG 355: Nivolumab to Tailored Radiation Therapy With Concomitant Cisplatin in the Treatment of Patients With Cervical Cancer

• Sponsor: Brown University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03527264
• Collaborator: Rhode Island Hospital (Other), The Miriam Hospital (Other), Women and Infants Hospital of Rhode Island (Other), Bristol-Myers Squibb (Industry)
• Enrollment: 4
• Locations: 2
• Arms: 4
• Actual Duration (Months): 24.2
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of the investigational drug in combination with radiation to learn whether the drug(s) works in treating a specific disease. In this study, researchers are studying three treatment arms, each using standard chemotherapy, with the drug cisplatin and radiation and the drug Nivolumab. Each treatment Arm will test the addition of Nivolumab at a different time point

Condition or Disease	Intervention/Treatment	Phase
Cervical Cancer	Drug: Nivolumab induction; Drug: Cisplatin; Radiation: Radiation; Drug: Nivolumab with chemoradiation; Drug: Nivolumab maintenance	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: BrUOG 355: A Pilot Feasibility Study Incorporating Nivolumab to Tailored Radiation Therapy With Concomitant Cisplatin in the Treatment of Patients With Cervical Cancer
• Actual Study Start Date: Nov 8, 2018
• Actual Primary Completion Date: Nov 13, 2020
• Actual Study Completion Date: Nov 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1A Nivolumab during Chemo/RT with whole pelvic RT	Drug: Nivolumab induction; 2 doses Nivolumab 240mg IV; Drug: Cisplatin; 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy.; Radiation: Radiation; Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field; Drug: Nivolumab with chemoradiation; Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.
Experimental: Cohort 1B Nivolumab during Chemo/RT with extended field	Drug: Nivolumab induction; 2 doses Nivolumab 240mg IV; Drug: Cisplatin; 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy.; Radiation: Radiation; Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field; Drug: Nivolumab with chemoradiation; Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.
Experimental: Cohort 2 Chemoradiation followed by Nivolumab Maintenance	Drug: Nivolumab induction; 2 doses Nivolumab 240mg IV; Drug: Cisplatin; 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy.; Radiation: Radiation; Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field; Drug: Nivolumab maintenance; Nivolumab 480 mg IV every 4 weeks for 2 years
Experimental: Cohort 3 Nivolumab during chemoradiation and then as maintenance	Drug: Nivolumab induction; 2 doses Nivolumab 240mg IV; Drug: Cisplatin; 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy.; Radiation: Radiation; Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field; Drug: Nivolumab with chemoradiation; Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.; Drug: Nivolumab maintenance; Nivolumab 480 mg IV every 4 weeks for 2 years

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival [From start of study treatment through date of study completion.]

   Number of patients that are alive without disease progression at time of analysis.

Secondary Outcome Measures

1. Recurrence Patterns [From start of study treatment through date of study completion.]

   Determination of the site of recurrence, loco-regional versus distant

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 18 years.

• ECOG performance status ≤2

• Patients with histologically confirmed advanced cervical cancer (any cell type): FIGO Clinical stages IB, IIA, IIB, IIIA, IIIB, IVA.

• Participants must have normal organ and marrow function as defined below:

1. absolute neutrophil count ≥1,500/mcL

2. platelets ≥100,000/mcL

3. total bilirubin within normal institutional limits

4. AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

5. creatinine Within normal institutional limits

• Neuropathy (sensory and motor) ≤ CTCAE v4.0 grade 1

• Patients with ureteral obstruction should undergo stent or nephrostomy tube placement prior to study entry. Any side effects or complications associated with stent placement that, in the opinion of the treating investigator, puts the patient at increased risk for treatment-related toxicity, must be resolved completely prior to study enrollment.

• Patients of child-bearing potential must have a negative serum pregnancy test prior to study entry (within 7 days prior to initiation of study treatment) and be practicing an effective form of contraception during study treatment and for 24 months (2 years) thereafter.

• Women should not breast-feed while on this study

• Patients must not be receiving any other investigational agent

• Ability to understand and the willingness to sign a written informed consent document.

• All patients with a history of hearing loss are required to have an audiogram within 28 days prior to initiating protocol therapy. If patient does not have a history of hearing loss this must be documented by treating physician.

Exclusion Criteria:

• Participants with visceral metastases, including brain metastases.

• Uncontrolled intercurrent illness

• Patients who have received previous pelvic or abdominal radiation, cytotoxic chemotherapy, or previous therapy of any kind for this malignancy

• Patients who have circumstances that will not permit completion of this study or the required follow-up as per the treating physician

• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer are excluded if there is any evidence of other malignancy being present within the last three years (2 years for invasive breast cancer). However, patients with a malignancy that is non-likely to require treatment, as per the treating physician, in the next 2 years, such as a completely resected, early stage breast cancer, are eligible. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.

• Prior treatment with immunotherapy for any cancer, including immune checkpoint inhibitors or anti-CTLA4 agents

• Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal transplantation, that would require modification of radiation fields as documented by treating physician

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rhode Island Hospital	Providence	Rhode Island	United States	02903
2	Women and Infants Hospital	Providence	Rhode Island	United States	02905

Sponsors and Collaborators

• Brown University
• Rhode Island Hospital
• The Miriam Hospital
• Women and Infants Hospital of Rhode Island
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Don Dizon, MD, Brown University Oncology Research Group (BrUOG)

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - May 11, 2020

More Information

Publications

None provided.

• Responsible Party: Brown University
• ClinicalTrials.gov Identifier: NCT03527264
• Other Study ID Numbers: BrUOG 355
• First Posted: May 17, 2018
• Last Update Posted: Apr 26, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Brown University: cervical cancer; Stage IB; Stage IIA; Stage IIB; Stage IIIA; Stage IIIB; Stage IVA
• Additional relevant MeSH terms: Uterine Cervical Neoplasms; Nivolumab

Study Results

Participant Flow

Arm/Group Title	Cohort 1A	Cohort 1B	Cohort 2	Cohort 3
Arm/Group Description	Nivolumab during Chemo/RT with whole pelvic RT Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.	Nivolumab during Chemo/RT with extended field Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.	Chemoradiation followed by Nivolumab Maintenance Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab maintenance: Nivolumab 480 mg IV every 4 weeks for 2 years	Nivolumab during chemoradiation and then as maintenance Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation. Nivolumab maintenance: Nivolumab 480 mg IV every 4 weeks for 2 years
Period Title: Overall Study
STARTED	3	1	0	0
COMPLETED	3	1	0	0
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1A	Cohort 1B	Cohort 2	Cohort 3	Total
Arm/Group Description	Nivolumab during Chemo/RT with whole pelvic RT Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.	Nivolumab during Chemo/RT with extended field Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.	Chemoradiation followed by Nivolumab Maintenance Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab maintenance: Nivolumab 480 mg IV every 4 weeks for 2 years	Nivolumab during chemoradiation and then as maintenance Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation. Nivolumab maintenance: Nivolumab 480 mg IV every 4 weeks for 2 years	Total of all reporting groups
Overall Participants	3	1	0	0	4
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 NaN
Between 18 and 65 years	1 33.3%	1 100%	2 Infinity
>=65 years	2 66.7%	0 0%	2 Infinity
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	66	54	63
Sex: Female, Male (Count of Participants)
Female	3 100%	1 100%	4 Infinity
Male	0 0%	0 0%	0 NaN
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 33.3%	0 0%	1 Infinity
Not Hispanic or Latino	2 66.7%	1 100%	3 Infinity
Unknown or Not Reported	0 0%	0 0%	0 NaN
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 NaN
Asian	0 0%	0 0%	0 NaN
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 NaN
Black or African American	0 0%	0 0%	0 NaN
White	2 66.7%	1 100%	3 Infinity
More than one race	0 0%	0 0%	0 NaN
Unknown or Not Reported	1 33.3%	0 0%	1 Infinity
Region of Enrollment (participants) [Number]
United States	3 100%	1 100%	4 Infinity

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival
Description	Number of patients that are alive without disease progression at time of analysis.
Time Frame	From start of study treatment through date of study completion.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1A	Cohort 1B
Arm/Group Description	Nivolumab during Chemo/RT with whole pelvic RT Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.	Nivolumab during Chemo/RT with extended field Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.
Measure Participants	3	1
Count of Participants [Participants]	2 66.7%	1 100%

2. Secondary Outcome

Title	Recurrence Patterns
Description	Determination of the site of recurrence, loco-regional versus distant
Time Frame	From start of study treatment through date of study completion.

Outcome Measure Data

Analysis Population Description

Only 1 patient on cohort 1A had recurrence within 3 years of study entry.

Arm/Group Title	Cohort 1A	Cohort 1B
Arm/Group Description	Nivolumab during Chemo/RT with whole pelvic RT Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.	Nivolumab during Chemo/RT with extended field Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.
Measure Participants	1	0
Loco-regional	1 33.3%	0 0%
Distant	0 0%	0 0%

Adverse Events

Time Frame	All adverse events were reported from the time a signed and dated ICF is obtained through study treatment completion, an average of 6 months.
Arm/Group Title	Cohort 1A		Cohort 1B
Arm/Group Description	Nivolumab during Chemo/RT with whole pelvic RT Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.		Nivolumab during Chemo/RT with extended field Nivolumab induction: 2 doses Nivolumab 240mg IV Cisplatin: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. Radiation: Total dose of 45 Gy in 25 fractions at 180 cGy/fx Whole pelvic or extended field Nivolumab with chemoradiation: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation.
All Cause Mortality
	Cohort 1A		Cohort 1B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/1 (0%)
Serious Adverse Events
	Cohort 1A		Cohort 1B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		1/1 (100%)
Gastrointestinal disorders
Nausea	1/3 (33.3%)		0/1 (0%)
Vomiting	1/3 (33.3%)		0/1 (0%)
General disorders
Fatigue	1/3 (33.3%)		0/1 (0%)
Generalized muscle weakness	1/3 (33.3%)		0/1 (0%)
Infections and infestations
Sepsis	1/3 (33.3%)		0/1 (0%)
Psychiatric disorders
Suicidal ideation	0/3 (0%)		1/1 (100%)
Vascular disorders
Hypotension	1/3 (33.3%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1A		Cohort 1B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/1 (100%)
Blood and lymphatic system disorders
Anemia	3/3 (100%)		1/1 (100%)
Gastrointestinal disorders
Nausea	2/3 (66.7%)		0/1 (0%)
Vomiting	2/3 (66.7%)		0/1 (0%)
Abdominal pain	1/3 (33.3%)		0/1 (0%)
Diarrhea	3/3 (100%)		1/1 (100%)
Rectal hemorrhage	0/3 (0%)		1/1 (100%)
Constipation	1/3 (33.3%)		0/1 (0%)
GERD	1/3 (33.3%)		0/1 (0%)
General disorders
Fatigue	1/3 (33.3%)		0/1 (0%)
Chills	1/3 (33.3%)		0/1 (0%)
Fever	1/3 (33.3%)		0/1 (0%)
Cough	1/3 (33.3%)		0/1 (0%)
Immune system disorders
Allergic reaction	0/3 (0%)		1/1 (100%)
Infections and infestations
Upper respiratory infection	2/3 (66.7%)		0/1 (0%)
Investigations
Weight loss	1/3 (33.3%)		0/1 (0%)
Lipase increased	1/3 (33.3%)		1/1 (100%)
Lymphocyte count decreased	3/3 (100%)		1/1 (100%)
White blood cell count decreased	3/3 (100%)		0/1 (0%)
Neutrophil count decreased	2/3 (66.7%)		0/1 (0%)
Aspartate aminotransferase increased	0/3 (0%)		1/1 (100%)
Alanine aminotransferase increased	0/3 (0%)		1/1 (100%)
Hypoalbuminemia	1/3 (33.3%)		1/1 (100%)
Platelet count decreased	2/3 (66.7%)		1/1 (100%)
Serum amylase increased	1/3 (33.3%)		0/1 (0%)
Serum creatinine increased	1/3 (33.3%)		0/1 (0%)
Hypocalcemia	1/3 (33.3%)		0/1 (0%)
Metabolism and nutrition disorders
Anorexia	1/3 (33.3%)		0/1 (0%)
Hyponatremia	2/3 (66.7%)		1/1 (100%)
Dehydration	2/3 (66.7%)		0/1 (0%)
Hypokalemia	2/3 (66.7%)		0/1 (0%)
Hyperglycemia	0/3 (0%)		1/1 (100%)
Hypomagnesemia	3/3 (100%)		1/1 (100%)
Hypophosphatemia	1/3 (33.3%)		0/1 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	1/3 (33.3%)		0/1 (0%)
Psychiatric disorders
Dizziness	1/3 (33.3%)		1/1 (100%)
Anxiety	1/3 (33.3%)		0/1 (0%)
Insomnia	1/3 (33.3%)		1/1 (100%)
Reproductive system and breast disorders
Pelvic pain	1/3 (33.3%)		0/1 (0%)
Respiratory, thoracic and mediastinal disorders
Hoarseness	1/3 (33.3%)		0/1 (0%)
Wheezing	1/3 (33.3%)		0/1 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/3 (33.3%)		0/1 (0%)
Vascular disorders
Hypotension	1/3 (33.3%)		0/1 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.