Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Rare Diseases

Uterine Cervical Neoplasms

Precancerous Conditions

Uterine Cervical Dysplasia

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Cervical Intraepithelial Neoplasia

Bone Density Conservation Agents

All Drugs and Chemicals

Zoledronic Acid

100 cc of saline with 4 mg of zoledronate intravenous (IV), over 20 minutes, for 3 doses one week apart

Treatment repeats every 21 days (one course) for up to 3 courses. In week 8, patients undergo surgical resection comprising loop excision or cone biopsy.

After completion of study treatment, patients are followed at week 10 by telephone.

100 cc of saline IV, over 20 minutes, for 3 doses one week apart

Treatment repeats every 21 days (one course) for up to 3 courses. In week 8, patients undergo surgical resection comprising loop excision or cone biopsy.

After completion of study treatment, patients are followed at week 10 by telephone.

Zoledronate

Placebo (Saline)

Karen Smith-McCune, MD, PhD

RATIONALE: Chemoprevention is the use of certain drugs to keep tumors from forming, growing, or coming back. Zoledronate may prevent the growth of cervical cancer by blocking blood flow to cervical intraepithelial neoplasia cells. The use of zoledronate may keep cancer from forming.

PURPOSE: This randomized is studying how well zoledronate works in treating patients with cervical intraepithelial neoplasia 2/3 or 3.

OBJECTIVES:

* Assess clinical response, in terms of lesion size and histological grade, of oledronate in patients with cervical intraepithelial neoplasia 2/3 or 3.

OUTLINE: This is a randomized, placebo-controlled, double-blind, pilot study. Patients are stratified according to degree of cervical intraepithelial neoplasia (CIN) (CIN2/3 vs CIN3). Patients are randomized to 1 of 2 treatment arms.

* Zoledronate: 100 cc of saline with 4 mg of Zoledronate intravenous (IV), over 20 minutes, for 3 doses one week apart
* Placebo: 100 cc of saline (IV), over 20 minutes, for 3 doses one week apart

In both arms, treatment repeats every 21 days for up to 3 courses. In week 8, patients undergo surgical resection comprising loop excision or cone biopsy.

After completion of study treatment, patients are followed at week 10 by telephone.

PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

Zoledronate in Treating Patients With Cervical Intraepithelial Neoplasia 2/3 or 3

An Exploratory Clinical Trial of Zoledronic Acid in Women With CIN 2/3 or 3

The primary objective is to determine whether Zoledronic Acid (ZA), when given to women with CIN 2/3 or 3 for two months prior to surgical excision, has a measurable impact on clinical response (lesion size and histological grade).

National Cancer Institute (NCI)

University of California, San Francisco

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Breast Neoplasms

Neoplasm Metastasis

Breast Diseases

Skin Diseases

Antineoplastic Agents

Anti-Infective Agents

Hormones

Everolimus

Exemestane

Radium Ra 223 dichloride

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Aromatase Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Up to 6 cycles of radium-223 dichloride 50kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

Up to 6 cycles of saline injection (placebo) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update)

Radium-223 dichloride (Xofigo, BAY88-8223)

Placebo (saline)

One 25 mg tablet once daily after a meal.

The recommended dose of everolimus administered in the study is 10 mg once daily with or without food.

Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.

Bayer Study Director

The objective of this study is to assess efficacy and safety of radium 223 dichloride in subjects with human epidermal growth factor receptor 2 (HER2) negative hormone receptor positive breast cancer with bone metastases treated with exemestane and everolimus

After implementation of CSP Amendment 10, only a limited number of subjects will remain in this study, in order to reduce the burden to study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, and OS. Once subjects are rolled over, the long-term safety will be collected and assessed entirely in the separate extended safety follow-up study.

Study of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus in Subjects With Bone Predominant HER2 Negative Hormone Receptor Positive Metastatic Breast Cancer

A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases

An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation participant after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.

Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause. Per Protocol Amendment 10, following primary analysis completion, further assessments were focused on safety, and only limited efficacy data including SSE and survival were collected and not designed to support reconsideration of the primary analysis efficacy conclusions. Accordingly, no formal statistical analyses were performed for primary and secondary efficacy outcomes in the final analysis. All primary and secondary efficacy outcome measures presented in this document came from the primary completion analysis.

The time from the date of randomization to the date of death due to any cause. Per Protocol Amendment 10, following primary analysis completion, further assessments were focused on safety, and only limited efficacy data including SSE and survival were collected and not designed to support reconsideration of the primary analysis efficacy conclusions. Accordingly, no formal statistical analyses were performed for primary and secondary efficacy outcomes in the final analysis. All primary and secondary efficacy outcome measures presented in this document came from the primary completion analysis.

Interval from the date of randomization to the date of opiate use

Time from randomization to the first date a participant experienced pain progression based on WPS. Pain progression was defined as an increase of 2 or more points in the BPI-SF "Worst pain in 24 hours" score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.

Time from the date of randomization to the date of the first cytotoxic chemotherapy

Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression). Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.

In the percentage of participants with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.

According to protocol amendment 10, all participants who completed the EOT visit will be transferred to a separate extended safety follow-up study for their remaining follow-up. Thus, no further post-treatment data were collected after protocol amendment 10.

Bayer

For All-Cause Mortality section, "Total Number Affected" are updated in final results posting. Deaths of this study 17096 participants who transferred to study 16996 (NCT02312960) for long-term follow-up were erroneously reported in the 17096 primary analysis disclosure. This has been corrected and only 17096 data is reported in this disclosure here. 16996 outcomes will be reported in the 16996 disclosure.

Participants were randomized to treatment with radium-223 dichloride, also with exemestane and everolimus and supportive care as per the local or institutional standard of practice

Radium-223 + EXE/EVE

Participants were randomized to treatment with placebo, also with exemestane and everolimus and supportive care as per the local or institutional standard of practice

Placebo + EXE/EVE

Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice

Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Intent-to-Treat Analysis Set (ITT analysis set): included all randomized participants

Due to reassessment of the Primary Completion date (PCD) conditions, PCD was moved back to 22 January 2020. Interim survival data on patients transferring from this study to study 16996 (NCT02312960), as of analysis cutoff, was pooled with this study's data to increase the reliability of efficacy results. This pooling was specified in a supplemental SAP dated 24 Jun 2020. All other primary and secondary analysis details were specified in the main study SAP dated 14 Feb 2020.

Therapeutic Area Head

The 1-sided null hypothesis that treatment with radium-223 dichloride does not result in superior SSE-FS to treatment with placebo in participant population was tested against the 1-sided alternative hypothesis that the treatment with radium-223 dichloride results in superior SSE-FS time to treatment the placebo. H0: SSE-FS Radium-223+Exemestane/Everolimus \<= SSE-FS Placebo+Exemestane/Everolimus, versus HA: SSE-FSRadium-223+Exemestane/Everolimus \> SSE-FS Placebo+Exemestane/Everolimus

Intent to treat analysis set: all randomized participants

Symptomatic Skeletal Event-free Survival (SSE-FS)

Overall Survival

Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice

Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane \[25-mg tablet once daily (after a meal)\], and everolimus \[10 mg once daily (with or without food)\]), and supportive care as per the local or institutional standard of practice

Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Time to Opiate Use for Cancer Pain

Participants with baseline WPS \> 8 were included in the analysis population but censored at Day 1.

Time to Pain Progression

ITT analysis set: included all randomized participants

Time to Cytotoxic Chemotherapy

Radiological Progression-free Survival (rPFS)

Safety analysis set with baseline WPS \>= 2: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo exemestane, or everolimus), and who in addition had baseline BPI-SF WPS \>= 2. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Percentage of Participants With Pain Improvement

Any TEAE

Serious TEAE

Radium-223/Placebo-related TEAEs

Exemestane-related TEAEs

Everolimus-related TEAEs

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

All system organ classes_Any_Grade 3

All system organ classes_Any_Grade 4

Blood and lymphatic system disorders_Any_Grade 3

Blood and lymphatic system disorders_Febrile neutropenia_Grade 3

Investigations_Any_Grade 4

Investigations_Neutrophil count decreased_Grade 4

Number of Participants With Post-treatment Chemotherapy Related Adverse Events

Anemia

Leukocytosis

Hemoglobin increased

Lymphocyte count decreased

Lymphocyte count increased

Neutrophil count decreased

Platelet count decreased

White blood cell decreased

Safety analysis set with at least one hematology lab assessment: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus), and who in addition had at least one hematology lab assessment. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Number of Participants With Hematological Toxicities: Worst Grade Under Treatment

Number of Participants With New Primary Malignancies

Number of Participants With Treatment-emergent Adverse Events (TEAEs) (From First Dosing Till Primary Analysis)

Number of Participants With Post-treatment Chemotherapy Related Adverse Events (From First Dosing Till Primary Analysis)

Number of Participants With Hematological Toxicities: Worst Grade Under Treatment (From First Dosing Till Primary Analysis)

Number of Participants With New Primary Malignancies During Study Treatment Till Primary Analysis

Overall Study

Pharmaceutical Solutions

Mitogens

Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks

Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks

Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update)

Prescribed by PI and was provided as long as patient can tolerate treatment. It must be prescribed as per local label in country participating.

Background hormonal therapy

The objective of this study was to assess efficacy and safety of radium-223 dichloride in subjects with human epidermal growth factor receptor 2 negative (HER2 negative) hormone receptor positive breast cancer with bone metastases treated with hormonal treatment background therapy

Study of Radium-223 Dichloride Versus Placebo and Hormonal Treatment as Background Therapy in Subjects With Bone Predominant HER2 (Human Epidermal Growth Factor Receptor 2) Negative Hormone Receptor Positive Metastatic Breast Cancer

A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride Versus Placebo When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases Treated With Hormonal Treatment Background Therapy

Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause

Time from randomization to death from any cause

Time from randomization to the first date a participants (only in participants with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) ranging from 0 to 10 and analgesic use. Pain progression is defined as an increase of 2 or more points in the "Worst pain in 24 hours" score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurs first

The percentage of participants (baseline WPS\>=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart

Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression)

Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake

AEs related to the study drug, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events (regardless of severity and relationship to study drug), and some symptoms needed for the characterization of an symptomatic skeletal event

Adverse events (AEs) included 1) any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake 2) AEs related to study treatment reported beyond 30 days after study medication, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events and and some symptoms needed for the characterization of an symptomatic skeletal event

Radium 223 Dichloride

Placebo

Race (NIH/OMB)

Intend-to-treat (ITT) analysis set: all randomized participants

Due to the premature enrollment discontinuation, reduced sample size, and potentially curtailed active follow up, the planned number of SSE FS events was not achieved, limiting the assessment of the primary efficacy endpoint.

The null hypothesis that both treatment groups have the same SSE-FS distribution will be tested against the alternative hypothesis that the distribution of SSE-FS time in radium-223 dichloride is different from the placebo group

Symptomatic Skeletal Event Free Survival (SSE-FS)

Safety analysis set: all randomized participants who received at least one study drug administration (radium 223 dichloride or placebo)

Participants in safety analysis set taken into account for this endpoint analysis

Pain Improvement Rate

Radium 223/Placebo related TEAEs

Safety analysis set: all randomized subjects who received at least one dose of study medication (radium 223 dichloride or placebo)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Zoledronate in Treating Patients With Cervical Intraepithelial Neoplasia 2/3 or 3	NCT00278434	Cervical Cancer Precancerous Co...	Zoledronate Placebo (Saline...	18 Years - 120 Years	University of California, San Francisco
Study of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus in Subjects With Bone Predominant HER2 Negative Hormone Receptor Positive Metastatic Breast Cancer	NCT02258451	Breast Neoplasm...	Radium-223 dich... Placebo (saline... Exemestane Everolimus	18 Years -	Bayer
Study of Radium-223 Dichloride Versus Placebo and Hormonal Treatment as Background Therapy in Subjects With Bone Predominant HER2 (Human Epidermal Growth Factor Receptor 2) Negative Hormone Receptor Positive Metastatic Breast Cancer	NCT02258464	Breast Neoplasm...	Radium-223 dich... Placebo (saline... Background horm...	18 Years -	Bayer
Zoledronate in Treating Patients With Cervical Intraepithelial Neoplasia 2/3 or 3	NCT00278434	Cervical Cancer Precancerous Co...	Zoledronate Placebo (Saline...	18 Years - 120 Years	University of California, San Francisco
Study of Radium-223 Dichloride Versus Placebo and Hormonal Treatment as Background Therapy in Subjects With Bone Predominant HER2 (Human Epidermal Growth Factor Receptor 2) Negative Hormone Receptor Positive Metastatic Breast Cancer	NCT02258464	Breast Neoplasm...	Radium-223 dich... Placebo (saline... Background horm...	18 Years -	Bayer

Spots Global Cancer Trial Database for placebo (saline)