Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never Smokers or Those With KRAS G12D
Study Details
Study Description
Brief Summary
The purpose of this study is to test the drug Bortezomib to see how well it works. The investigators want to find out what effects, good or bad, it has on patients with a limited smoking history or who have a specific mutation associated with their lung cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Bortezomib Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. |
Drug: Bortezomib
Drug: Acyclovir
|
Outcome Measures
Primary Outcome Measures
- Radiographic Response Rate [2 years]
The following evaluations will be conducted to assess the efficacy of bortezomib - radiographic response rate by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Secondary Outcome Measures
- Progression Free Survival [2 years]
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
- Participants Evaluated for Toxicity [2 years]
Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE v4.0,).
- Overall Survival [2 years]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Pathologic or cytologic evidence of non-small cell lung cancer (NSCLC)
-
Documented KRAS mutation
-
History of smoking < 100 cigarettes (never-smoker) OR patient with a KRAS G12D mutation regardless of smoking history
-
Clinical stage IIIB/IV or recurrent/medically inoperable NSCLC
-
Age ≥ 18 years
-
Three (3) weeks since last chemotherapy, and three (3) weeks since prior radiation therapy and recovered from treatment
-
Karnofsky performance status ≥ 70%
-
Adequate hematologic, and/or hepatic function WBC ≥ 3,000/ul or absolute neutrophil count ≥ 1,000/ul Hemoglobin ≥ 9.0 g/dl Platelet count ≥ 100,000/ul AST ≤ 2.0 X ULN (upper limit of normal)
-
Total bilirubin ≤1.5 x ULN Measurable indicator lesions by RECIST v1.1 criteria.
-
Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
-
Female subject is either postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse.
-
Male subjects must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse.
Exclusion Criteria:
- Uncontrolled central nervous system metastases defined as any lesion which is either
- symptomatic, or requiring escalating doses of corticosteroids
-
Significant medical history or unstable medical condition such as uncontrolled diabetes myocardial infarction within 6 months prior to enrollment New York Heart Association Class III or IV heart failure severe uncontrolled ventricular arrythmias uncontrolled angina ECG evidence of acute ischemia or active conduction system abnormalities
-
Baseline ≥ grade 2 peripheral neuropathy by CTCAE v 4.0 (Appendix B)
-
Known hypersensitivity to boron or mannitol
-
Female patients who are pregnant/lactating or have a positive serum or urine β-hCG pregnancy test
-
Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
-
No active concurrent malignancy, with the exception of in-situ malignancy completely resected basal cell carcinoma or squamous cell carcinomas of the skin low-risk prostate cancer after curative therapy
-
Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Memoral Sloan Kettering Cancer Center | Basking Ridge | New Jersey | United States | |
| 2 | Memorial Sloan Kettering Cancer Center @ Suffolk | Commack | New York | United States | 11725 |
| 3 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 4 | Memorial Sloan Kettering Cancer Center at Mercy Medical Center | Rockville Centre | New York | United States | 11570 |
| 5 | Memoral Sloan Kettering Cancer Center at Phelps | Sleepy Hollow | New York | United States | 10591 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
- Millennium Pharmaceuticals, Inc.
Investigators
- Principal Investigator: Gregory Riely, MD, PhD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 12-222
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Bortezomib |
|---|---|
| Arm/Group Description | Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. |
| Period Title: Overall Study | |
| STARTED | 17 |
| COMPLETED | 16 |
| NOT COMPLETED | 1 |
Baseline Characteristics
| Arm/Group Title | Bortezomib |
|---|---|
| Arm/Group Description | Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. |
| Overall Participants | 17 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
67
|
| Sex: Female, Male (Count of Participants) | |
| Female |
8
47.1%
|
| Male |
9
52.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1
5.9%
|
| Not Hispanic or Latino |
16
94.1%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
3
17.6%
|
| White |
13
76.5%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
1
5.9%
|
| Region of Enrollment (Count of Participants) | |
| United States |
17
100%
|
Outcome Measures
| Title | Radiographic Response Rate |
|---|---|
| Description | The following evaluations will be conducted to assess the efficacy of bortezomib - radiographic response rate by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Bortezomib |
|---|---|
| Arm/Group Description | Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. |
| Measure Participants | 17 |
| Partial Response |
1
5.9%
|
| Stable Disease |
6
35.3%
|
| Progression of Disease |
10
58.8%
|
| Title | Progression Free Survival |
|---|---|
| Description | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Bortezomib |
|---|---|
| Arm/Group Description | Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. |
| Measure Participants | 17 |
| Median (95% Confidence Interval) [months] |
1
|
| Title | Participants Evaluated for Toxicity |
|---|---|
| Description | Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE v4.0,). |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Bortezomib |
|---|---|
| Arm/Group Description | Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. |
| Measure Participants | 17 |
| Count of Participants [Participants] |
17
100%
|
| Title | Overall Survival |
|---|---|
| Description | |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Bortezomib |
|---|---|
| Arm/Group Description | Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. |
| Measure Participants | 17 |
| Median (95% Confidence Interval) [months] |
13
|
Adverse Events
| Time Frame | 2 years | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Bortezomib | |
| Arm/Group Description | Bortezomib will be administered by subcutaneous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) at 1.3 mg/m2/dose followed by a 10-day rest period for a 21 day cycle. Dose modifications are permitted as per a prescribed algorithm. Acyclovir at 400mg daily is recommended as prophylaxis for herpes zoster. Restaging scans, with evaluation of response, will be done every 2 cycles (6 weeks of treatment ± 7 days). Treatment will continue until clinical disease progression, unacceptable toxicity, treatment delay > 2 weeks, or at the discretion of the treating physician or patient. | |
All Cause Mortality |
||
| Bortezomib | ||
| Affected / at Risk (%) | # Events | |
| Total | 12/17 (70.6%) | |
Serious Adverse Events |
||
| Bortezomib | ||
| Affected / at Risk (%) | # Events | |
| Total | 4/17 (23.5%) | |
| Blood and lymphatic system disorders | ||
| Leukocytosis | 1/17 (5.9%) | |
| General disorders | ||
| Fever | 1/17 (5.9%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 2/17 (11.8%) | |
| Pneumonitis | 1/17 (5.9%) | |
Other (Not Including Serious) Adverse Events |
||
| Bortezomib | ||
| Affected / at Risk (%) | # Events | |
| Total | 16/17 (94.1%) | |
| Endocrine disorders | ||
| Hypothyroidism | 1/17 (5.9%) | |
| Eye disorders | ||
| Eye pain | 1/17 (5.9%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 6/17 (35.3%) | |
| Constipation | 4/17 (23.5%) | |
| Nausea | 4/17 (23.5%) | |
| Mucositis oral | 2/17 (11.8%) | |
| Vomiting | 2/17 (11.8%) | |
| Dry mouth | 1/17 (5.9%) | |
| Hemorrhoids | 1/17 (5.9%) | |
| General disorders | ||
| Fatigue | 8/17 (47.1%) | |
| Localized edema | 3/17 (17.6%) | |
| Fever | 2/17 (11.8%) | |
| Injection site reaction | 2/17 (11.8%) | |
| Flu like symptoms | 1/17 (5.9%) | |
| Investigations | ||
| Platelet count decreased | 2/17 (11.8%) | |
| Metabolism and nutrition disorders | ||
| Anorexia | 4/17 (23.5%) | |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 2/17 (11.8%) | |
| Pain in extremity | 1/17 (5.9%) | |
| Nervous system disorders | ||
| Headache | 3/17 (17.6%) | |
| Peripheral motor neuropathy | 2/17 (11.8%) | |
| Peripheral sensory neuropathy | 2/17 (11.8%) | |
| Psychiatric disorders | ||
| Depression | 1/17 (5.9%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 1/17 (5.9%) | |
| Skin and subcutaneous tissue disorders | ||
| Papulopustular rash | 4/17 (23.5%) | |
| Rash maculo-papular | 1/17 (5.9%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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.
Results Point of Contact
| Name/Title | Gregory Riely, MD, PhD |
|---|---|
| Organization | Memorial Sloan Kettering Cancer Center |
| Phone | 646-608-3913 |
| rielyg@mskcc.org |
- 12-222