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A Study of Alectinib in RET-rearranged Non-small Cell Lung Cancer or RET-mutated Thyroid 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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03131206
Recruitment Status : Terminated (Study closed due to slow accrual and lack of efficacy.)
First Posted : April 27, 2017
Results First Posted : November 25, 2019
Last Update Posted : November 25, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Mark Awad, MD, Dana-Farber Cancer Institute

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions ALK-positive Non-small Cell Lung Cancer (NSCLC)
RET-positive Non-small Cell Lung Cancer (NSCLC)
RET-positive Thyroid Cancer
Intervention Drug: Alectinib
Enrollment 5
Recruitment Details  
Pre-assignment Details The Phase 1 portion of the study includes 3 dose levels that can be explored: Dose Level 1 (starting dose), Dose Level -1, and Dose Level 2. This study enrolled only to Dose Level 1, therefore the baseline and outcome measures presented are for the DL1 participants only.
Arm/Group Title Phase 1 RP2D of Alectinib Phase 2 Cohort A Phase 2 Cohort B Phase 2 Cohort C
Hide Arm/Group Description Alectinib will be administered orally twice daily. A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days. Participants with RET-positive NSCLC with no previous history of RET-TKI therapy. Participants with RET-positive NSCLC with previous history of RET-TKI therapy. Participants with RET-positive thyroid cancer
Period Title: Dose Level 1 (600mg BID 7d, 900mg BID)
Started 5 0 0 0
Completed 5 0 0 0
Not Completed 0 0 0 0
Period Title: Dose Level 2 (900mg BID 7d, 1200mg BID)
Started 0 0 0 0
Completed 0 0 0 0
Not Completed 0 0 0 0
Arm/Group Title Phase 1 RP2D of Alectinib Phase 2 Cohort A Phase 2 Cohort B Phase 2 Cohort C Total
Hide Arm/Group Description Dose Level 1 (starting dose) Participants with RET-positive NSCLC with no previous history of RET-TKI therapy. Participants with RET-positive NSCLC with previous history of RET-TKI therapy. Participants with RET-positive thyroid cancer Total of all reporting groups
Overall Number of Baseline Participants 5 0 0 0 5
Hide Baseline Analysis Population Description
All 5 patients enrolled contributed demographic data.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 5 participants 0 participants 0 participants 0 participants 5 participants
60
(36 to 64)
60
(36 to 64)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 0 participants 0 participants 0 participants 5 participants
Female
3
  60.0%
3
  60.0%
Male
2
  40.0%
2
  40.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 0 participants 0 participants 0 participants 5 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
Not Hispanic or Latino
4
  80.0%
4
  80.0%
Unknown or Not Reported
1
  20.0%
1
  20.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 0 participants 0 participants 0 participants 5 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
White
4
  80.0%
4
  80.0%
More than one race
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
  20.0%
1
  20.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 5 participants 0 participants 0 participants 0 participants 5 participants
5 5
Mutation status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 5 participants 0 participants 0 participants 0 participants 5 participants
RET-rearranged NSCLC 4 4
ALK-rearranged NSCLC 1 1
[1]
Measure Description: RET rearrangement or ALK rearrangement, as determined by a CLIA-certified test
1.Primary Outcome
Title Maximum Tolerated Dose (Phase 1)
Hide Description The maximally administered dose (MAD) of the study medication will be defined as the dose level where at least two subjects develop toxicities consistent with a DLT definition. In this situation, the dose level immediately below the MAD will be defined as the MTD.
Time Frame 28 Days
Hide Outcome Measure Data
Hide Analysis Population Description
5 patients were analyzed for the MTD, but the MTD was not reached due to incomplete enrollment (6 patients required to evaluate MTD, per protocol; study closed to enrollment after 5 participants were enrolled). There were no participants analyzed in the Phase 2 portion of the study (Cohorts A, B, and C), hence why those fields are NA.
Arm/Group Title Phase 1 RP2D of Alectinib Cohort A Cohort B Cohort C
Hide Arm/Group Description:

The investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have NSCLC, not everyone who participates in this research study will receive the same dose of the study drug. The dosage will depend on the number of participants who have been enrolled in the study and how well the dosage has been tolerated.

  • Alectinib
  • Oral, BID
  • A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged NSCLC with no previous history of RET-TKI therapy.

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged NSCLC with previous history of RET-TKI therapy.

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged thyroid cancer

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.
Overall Number of Participants Analyzed 5 0 0 0
Measure Type: Number
Unit of Measure: mg
NA [1] 
[1]
MTD could not be evaluated as only 5 subjects were enrolled; per protocol, 6 subjects are required to evaluate MTD.
2.Primary Outcome
Title Objective Response Rate
Hide Description Preliminary evaluation of objective response rate (ORR) of alectinib was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Per RECIST v1.1 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 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Five participants were enrolled to the Phase 1 portion of the study and had imaging assessments performed; these 5 participants were evaluable for response rate.
Arm/Group Title Phase 1 RP2D of Alectinib Cohort A Cohort B Cohort C
Hide Arm/Group Description:

The investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have NSCLC, not everyone who participates in this research study will receive the same dose of the study drug. The dosage will depend on the number of participants who have been enrolled in the study and how well the dosage has been tolerated.

  • Alectinib
  • Oral, BID
  • A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged NSCLC with no previous history of RET-TKI therapy.

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged NSCLC with previous history of RET-TKI therapy.

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged thyroid cancer

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.
Overall Number of Participants Analyzed 5 0 0 0
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
20
(0.52 to 71.63)
3.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve (AUC) of Alectinib
Hide Description AUC pharmacokinetic parameters will be estimated using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time Frame 4 months
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Progression Free Survival
Hide Description Progression evaluated using RECIST 1.1 Criteria
Time Frame 2 Years
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Overall Survival
Hide Description Overall survival is recorded from start of enrollment through study completion.
Time Frame OS was calculated at the time of analysis, which was approximately 22 months after the study opened to enrollment.
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants alive at time of analysis.
Arm/Group Title Phase 1 RP2D of Alectinib Cohort A Cohort B Cohort C
Hide Arm/Group Description:

The investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have NSCLC, not everyone who participates in this research study will receive the same dose of the study drug. The dosage will depend on the number of participants who have been enrolled in the study and how well the dosage has been tolerated.

  • Alectinib
  • Oral, BID
  • A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged NSCLC with no previous history of RET-TKI therapy.

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged NSCLC with previous history of RET-TKI therapy.

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.

Participants with RET-rearranged thyroid cancer

  • Alectinib
  • Oral, BID, participants will receive the RP2D identified during Phase 1.
  • Each treatment cycle will be defined as 28 consecutive days.

Alectinib: -- Oral, BID

  • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.
Overall Number of Participants Analyzed 5 0 0 0
Measure Type: Count of Participants
Unit of Measure: Participants
1
  20.0%
6.Secondary Outcome
Title Duration of Response
Hide Description Response evaluated using RECIST 1.1 Criteria
Time Frame 2 Years
Outcome Measure Data Not Reported
7.Secondary Outcome
Title Peak Plasma Concentration (Cmax) of Alectinib
Hide Description Cmax pharmacokinetic parameters will be estimated using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time Frame 4 months
Outcome Measure Data Not Reported
Time Frame Adverse events were collected for all participants from first dose through the follow-up period. AE data was collected for approximately 22 months on this study.
Adverse Event Reporting Description AE data is available for the 5 patients enrolled to the Phase I portion of the study. Since the study closed early, no participants were enrolled to Phase 2 Cohorts A, B, or C, and AE and mortality data are not available.
 
Arm/Group Title Phase 1 RP2D of Alectinib Phase 2 Cohort A Phase 2 Cohort B Phase 2 Cohort C
Hide Arm/Group Description

The investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have NSCLC, not everyone who participates in this research study will receive the same dose of the study drug. The dosage will depend on the number of participants who have been enrolled in the study and how well the dosage has been tolerated. A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.

The AE data presented here includes all 5 participants which were enrolled to the Phase 1 portion of the study, to Dose Level 1.

Participants with RET-positive NSCLC with no previous history of RET-TKI therapy. No participants were enrolled to Cohort A. Participants with RET-positive NSCLC with previous history of RET-TKI therapy. No participants were enrolled to Cohort B. Participants with RET-positive thyroid cancer. No participants were enrolled to Cohort C.
All-Cause Mortality
Phase 1 RP2D of Alectinib Phase 2 Cohort A Phase 2 Cohort B Phase 2 Cohort C
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/5 (80.00%)      0/0      0/0      0/0    
Hide Serious Adverse Events
Phase 1 RP2D of Alectinib Phase 2 Cohort A Phase 2 Cohort B Phase 2 Cohort C
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/5 (0.00%)      0/0      0/0      0/0    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Phase 1 RP2D of Alectinib Phase 2 Cohort A Phase 2 Cohort B Phase 2 Cohort C
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/5 (100.00%)      0/0      0/0      0/0    
Blood and lymphatic system disorders         
Anemia  1  2/5 (40.00%)  7 /0  /0  /0 
Cardiac disorders         
Chest pain - cardiac  1  1/5 (20.00%)  1 /0  /0  /0 
Sinus bradycardia  1  1/5 (20.00%)  1 /0  /0  /0 
Sinus tachycardia  1  1/5 (20.00%)  1 /0  /0  /0 
Gastrointestinal disorders         
Abdominal pain  1  1/5 (20.00%)  1 /0  /0  /0 
Constipation  1  1/5 (20.00%)  1 /0  /0  /0 
Diarrhea  1  1/5 (20.00%)  1 /0  /0  /0 
Gastrointestinal disorders - Other  1  1/5 (20.00%)  2 /0  /0  /0 
Nausea  1  1/5 (20.00%)  1 /0  /0  /0 
Stomach pain  1  1/5 (20.00%)  1 /0  /0  /0 
General disorders         
Edema limbs  1  1/5 (20.00%)  3 /0  /0  /0 
Fatigue  1  3/5 (60.00%)  3 /0  /0  /0 
Pain  1  2/5 (40.00%)  3 /0  /0  /0 
Investigations         
Alkaline phosphatase increased  1  2/5 (40.00%)  3 /0  /0  /0 
Blood bilirubin increased  1  1/5 (20.00%)  3 /0  /0  /0 
CPK increased  1  1/5 (20.00%)  4 /0  /0  /0 
Neutrophil count decreased  1  1/5 (20.00%)  1 /0  /0  /0 
Weight loss  1  1/5 (20.00%)  1 /0  /0  /0 
Metabolism and nutrition disorders         
Anorexia  1  2/5 (40.00%)  2 /0  /0  /0 
Hypernatremia  1  1/5 (20.00%)  1 /0  /0  /0 
Hypoalbuminemia  1  2/5 (40.00%)  4 /0  /0  /0 
Hypocalcemia  1  1/5 (20.00%)  3 /0  /0  /0 
Hypokalemia  1  3/5 (60.00%)  4 /0  /0  /0 
Hypomagnesemia  1  1/5 (20.00%)  1 /0  /0  /0 
Hyponatremia  1  1/5 (20.00%)  1 /0  /0  /0 
Hypophosphatemia  1  1/5 (20.00%)  1 /0  /0  /0 
Metabolism and nutrition disorders - Other  1  1/5 (20.00%)  3 /0  /0  /0 
Musculoskeletal and connective tissue disorders         
Back pain  1  2/5 (40.00%)  2 /0  /0  /0 
Flank pain  1  1/5 (20.00%)  2 /0  /0  /0 
Generalized muscle weakness  1  1/5 (20.00%)  1 /0  /0  /0 
Musculoskeletal and connective tissue disorder - Other  1  1/5 (20.00%)  1 /0  /0  /0 
Nervous system disorders         
Concentration impairment  1  2/5 (40.00%)  2 /0  /0  /0 
Headache  1  1/5 (20.00%)  1 /0  /0  /0 
Lethargy  1  1/5 (20.00%)  1 /0  /0  /0 
Memory impairment  1  1/5 (20.00%)  1 /0  /0  /0 
Peripheral sensory neuropathy  1  1/5 (20.00%)  1 /0  /0  /0 
Psychiatric disorders         
Anxiety  1  1/5 (20.00%)  2 /0  /0  /0 
Confusion  1  2/5 (40.00%)  2 /0  /0  /0 
Delirium  1  1/5 (20.00%)  1 /0  /0  /0 
Insomnia  1  1/5 (20.00%)  1 /0  /0  /0 
Renal and urinary disorders         
Hematuria  1  1/5 (20.00%)  2 /0  /0  /0 
Respiratory, thoracic and mediastinal disorders         
Cough  1  1/5 (20.00%)  1 /0  /0  /0 
Dyspnea  1  3/5 (60.00%)  3 /0  /0  /0 
Hypoxia  1  1/5 (20.00%)  2 /0  /0  /0 
Postnasal drip  1  1/5 (20.00%)  1 /0  /0  /0 
Skin and subcutaneous tissue disorders         
Rash maculo-papular  1  1/5 (20.00%)  1 /0  /0  /0 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Mark Awad, MD, PhD
Organization: Dana-Farber Cancer Institute
Phone: 6176323468
EMail: mark_awad@dfci.harvard.edu
Layout table for additonal information
Responsible Party: Mark Awad, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03131206    
Other Study ID Numbers: 17-080
First Submitted: April 19, 2017
First Posted: April 27, 2017
Results First Submitted: August 23, 2019
Results First Posted: November 25, 2019
Last Update Posted: November 25, 2019