Single-arm Study With Bimiralisib in Patients With HNSCC Harboring NOTCH1 Loss of Function Mutations
Study Details
Study Description
Brief Summary
Preclinical data and limited clinical evidence suggest that Head and Neck Squameous Cell Carcinoma tumors harboring certain mutations may respond well to PI3K/mTOR inhibition (phosphatidylinositol-3-kinase/ mammalian target of rapamycin inhibition).
The current study enrolls patients with refractory and / or metastatic Head and Neck Squameous Cell Carcinoma based on the mutational status of their disease to assess the response to treatment with bimiralisib, an orally available pan-PI3K/mTOR inhibitor (phosphatidylinositol-3-kinase/ mammalian target of rapamycin inhibitor).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Open single arm Bimiralisib capsules orally |
Drug: Bimiralisib
Bimiralisib capsules
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Objective Response Rate (ORR) [At 6 and 12 weeks after the start of therapy (± 3 days)]
Radiological tumor assessments were performed by computed tomography (CT) or magnetic resonance imaging (MRI) according to a standard protocol. ORR: comprised of all patients who achieved a confirmed partial or a confirmed complete response per RECIST 1.1
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Histologically or cytological confirmed diagnosis of Head and Neck Squameous Cell Carcinoma, for which no standard curative or life prolonging therapy is available
-
Available CLIA-certified sequencing results of the NOTCH gene in Head and Neck Squameous Cell Carcinoma (HNSCC) tumor material. The tumor must harbor a NOTCH1 LOF mutation as confirmed by central review (MD Anderson Cancer Center, MDACC)
-
ECOG performance status of ≤ 2
-
Adequate bone marrow, liver, and renal functions
-
Measurable disease according to RECIST version 1.1
-
Patients of reproductive potential must agree to use effective contraception from screening until 90 days after discontinuing study treatment.
Exclusion Criteria:
-
Has received any anti-cancer treatment including hormonal and investigational agents within 21 days prior to first dose of bimiralisib.
-
Major surgery within 28 days prior to first dose of bimiralisib or persisting side effects that have not improved to NCI-CTCAE grade 1 or better.
-
Pregnant or nursing (lactating) women.
-
Poorly controlled diabetes mellitus, steroid-induced diabetes mellitus
-
Has other active malignancies that require systemic treatment.
-
Has a known history of HIV infection
-
Any of the following cardiac abnormalities:
-
History of, or current, documented congestive heart failure (New York heart association functional classification iii - iv), documented cardiomyopathy
-
Symptomatic (NYHA class II or higher) left ventricular ejection fraction (LVEF) < 40% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (echo)
-
Myocardial infarction ≤ 6 months prior to enrolment
-
Unstable angina pectoris
-
Serious uncontrolled cardiac arrhythmia
-
Symptomatic pericarditis
-
Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug.
-
Patient has a history of non-compliance to medical regimen or inability to grant consent.
-
Medically documented history of an active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) or ≥ CTCAE grade 3 anxiety
-
History of interstitial pneumonitis or patients who require chronic oxygen supplementation.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | M.D. Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- M.D. Anderson Cancer Center
Investigators
- Principal Investigator: Faye M Johnson, MD,PhD, MD Anderson Cancer Center Recruiting, Houston, Texas, US 77030
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 2018-1003 (PQR309-009)
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Bimilralisib |
|---|---|
| Arm/Group Description | Bimiralisib capsules orally. All patients received 140 mg bimiralisib (PQR309) 140 mg orally once daily on two consecutive days followed by five days without treatment weekly until unacceptable toxicity, tumor progression, patient's request for withdrawal, investigator judgment, or death. |
| Period Title: Overall Study | |
| STARTED | 8 |
| Confirmed Partial Response | 1 |
| COMPLETED | 6 |
| NOT COMPLETED | 2 |
Baseline Characteristics
| Arm/Group Title | Bimiralisib Treatment |
|---|---|
| Arm/Group Description | Bimiralisib capsules (140 mg) orally once daily on 2 consecutive days followed by 5 days without treatment weekly. |
| Overall Participants | 8 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
65.5
|
| Sex: Female, Male (Count of Participants) | |
| Female |
2
25%
|
| Male |
6
75%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
0
0%
|
| Not Hispanic or Latino |
8
100%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| United States |
8
100%
|
Outcome Measures
| Title | Objective Response Rate (ORR) |
|---|---|
| Description | Radiological tumor assessments were performed by computed tomography (CT) or magnetic resonance imaging (MRI) according to a standard protocol. ORR: comprised of all patients who achieved a confirmed partial or a confirmed complete response per RECIST 1.1 |
| Time Frame | At 6 and 12 weeks after the start of therapy (± 3 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Open Single Arm |
|---|---|
| Arm/Group Description | Bimiralisib capsules orally Bimiralisib: Bimiralisib capsules |
| Measure Participants | 6 |
| Count of Participants [Participants] |
1
12.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Open Single Arm |
|---|---|---|
| Comments | The primary endpoint was to determine the objective response rate of patients with R/M HNSCC harboring NOTCH1 LOF mutations to oral bimiralisib using RECIST v1.1. We used a Simon's optimal two-stage design. In order to have 80% power to detect a response rate of 30%, (one-sided α=0.05 and β=0.20), we planned to enroll up to 10 patients in the first stage. If ≥ 2 patients had an objective response, then the study would enroll an additional 19 patients in the second stage. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percent with objective response |
| Estimated Value | 17 | |
| Confidence Interval |
(2-Sided) 95% 1 to 58 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | From the first dose of study drug (bimiralisib) until 30 days after the last dose of bimiralisib. | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Open Single Arm | |
| Arm/Group Description | Bimiralisib capsules orally Bimiralisib: Bimiralisib capsules | |
All Cause Mortality |
||
| Open Single Arm | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/8 (25%) | |
Serious Adverse Events |
||
| Open Single Arm | ||
| Affected / at Risk (%) | # Events | |
| Total | 5/8 (62.5%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 1/8 (12.5%) | 1 |
| General disorders | ||
| Disease Progression | 1/8 (12.5%) | 1 |
| Infections and infestations | ||
| Skin Infection | 1/8 (12.5%) | 1 |
| Osteomyelitis | 1/8 (12.5%) | 1 |
| Sepsis | 1/8 (12.5%) | 1 |
| Investigations | ||
| Hyperglycemia | 2/8 (25%) | 2 |
| Alanine aminotransferase increased | 1/8 (12.5%) | 1 |
| Renal and urinary disorders | ||
| Renal Injury | 1/8 (12.5%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Aspiration Pneumonia | 1/8 (12.5%) | 1 |
| Acute Respiratory Distress | 1/8 (12.5%) | 1 |
| Laryngeal Stenosis | 1/8 (12.5%) | 1 |
| Vascular disorders | ||
| Hemorrhage | 1/8 (12.5%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Open Single Arm | ||
| Affected / at Risk (%) | # Events | |
| Total | 8/8 (100%) | |
| Blood and lymphatic system disorders | ||
| Platelet count decreased | 1/8 (12.5%) | 1 |
| Ear and labyrinth disorders | ||
| Tinnitus | 1/8 (12.5%) | 1 |
| Gastrointestinal disorders | ||
| Nausea | 2/8 (25%) | 2 |
| vomiting | 1/8 (12.5%) | 1 |
| Diarrhea | 1/8 (12.5%) | 1 |
| General disorders | ||
| Fatigue | 2/8 (25%) | 3 |
| Investigations | ||
| Blood glucose increased | 1/8 (12.5%) | 1 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 1/8 (12.5%) | 1 |
| Dehydration | 1/8 (12.5%) | 1 |
| Renal and urinary disorders | ||
| Blood creatinine increased | 1/8 (12.5%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 2/8 (25%) | 2 |
| Dry skin | 1/8 (12.5%) | 1 |
| Pruritis | 1/8 (12.5%) | 1 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Dr. Faye Johnson |
|---|---|
| Organization | MD Anderson Cancer Center |
| Phone | 7137922121 |
| fmjohns@mdanderson.org |
- 2018-1003 (PQR309-009)