A clinical study to investigate the safety and efficacy of RXDX-101 in patients with locally Advanced or Metastatic Cancer

• Register: EUCTR
• Last refreshed on: 17 August 2015
• Main ID: EUCTR2014-001326-15-GB
• Date of registration: 23/12/2014
• Prospective Registration: Yes
• Primary sponsor: Ignyta, Inc.
• Public title: A clinical study to investigate the safety and efficacy of RXDX-101 in patients with locally Advanced or Metastatic Cancer
• Scientific title: A Phase 1/2a, Multicenter, Open-Label Study of Oral RXDX-101 in Adult Patients with Locally Advanced or Metastatic Cancer Confirmed to be Positive for TrkA, TrkB, TrkC, ROS1, or ALK Molecular Alterations
• Date of first enrolment: 25/02/2015
• Target sample size: 160
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-001326-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1

Countries of recruitment

France, Italy, Korea, Republic of, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trial Information Desk
• Affiliation: Ignyta, Inc.

• Name: Clinical Trial Information Desk
• Affiliation: Ignyta, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Willing and able to provide written IRB/IEC-approved Informed Consent.

2. Have histologically or cytologically confirmed diagnosis of relapsed or refractory locally advanced or metastatic solid tumors for whom no alternative effective standard therapy is available or for whom standard therapy is considered unsuitable or intolerable.
For Phase 1: Although it is preferred to enroll patients with solid tumors harboring a TrkA, TrkB, TrkC, ROS1, or ALK molecular alteration, this will not be an enrollment requirement.

For Phase 2a: it is mandatory to enroll patients with solid tumors harboring a TrkA, TrkB, TrkC, ROS1 or ALK molecular alteration (as defined in Biomarker Assessments):
• Cohort #1: express TrkA with an associated molecular alteration.
• Cohort #2: express TrkB with an associated molecular alteration.
• Cohort #3: express TrKC with an associated molecular alteration.
• Cohort #4a: patients with locally advanced or metastatic solid tumors that express ALK with an associated molecular alteration who are naïve to prior treatment with ALK inhibitors. Patients with locally advanced or metastatic NSCLC who have not received prior therapy with crizotinib or another ALK inhibitor will be excluded from this cohort, except in countries where patients do not have access to approved ALK inhibitors for the treatment of NSCLC.
• Cohort #4b: patients with locally advanced or metastatic solid tumors that express ALK with an associated molecular alteration who have received prior treatment with one or more ALK inhibitor. If a patient received one or more ALK inhibitors, then the patient must undergo a tumor biopsy following prior therapy.
Cohort #5: patients with locally advanced or metastatic solid tumors that express ROS1 with an associated molecular alteration.

3. Tumor tissue available for analysis is not required in the Phase 1 segment but is mandatory for the Phase 2a segment. Only non-CNS lesions may be re-biopsied and must incur minimal risk to patients (e.g., percutaneous biopsy).

4. Measurable disease according to RECIST version 1.1. is not required in the Phase 1 segment but is mandatory for the Phase 2a segment.

5. Prior cancer therapy is allowed, including crizotinib, ceritinib, and investigational drugs. At the time of treatment start, at least 2-4 weeks must have elapsed after prior cytotoxic chemotherapy (at least 6 weeks for nitrosureas, mitomycin C and liposomal doxorubicin). In the absence of toxicity, 7 days must have elapsed since completion of prior non-cytotoxic cancer therapy. At least 4 weeks must have elapsed since completion of antibody-directed therapy.

6. Prior radiotherapy is allowed if >14 days have elapsed since end of treatment.

7. Patients with controlled asymptomatic CNS involvement are allowed in absence of therapy with anticonvulsants (anticonvulsant therapy must have been discontinued for at least 4 weeks). Patients not requiring or requiring steroids at stable dose (= 4 mg/day dexamethasone or equivalent) for at least 2 weeks are eligible.

8. Patients who have received brain irradiation must have completed whole brain radiotherapy and stereotactic radiosurgery at least 4 weeks prior to enrollment.

9. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to NCI CTCAE (Version 4.03) Grade = 1 or to the baseline laboratory values as defined in Inclusion Criterion Number 13.

10. Eastern Cooperative Oncology Group (EC
Exclusion criteria:
1. Current participation in another therapeutic clinical trial.
2. Known symptomatic brain metastases or leptomeningeal involvement as assessed by MRI or contrast CT scan examination. Patients with asymptomatic leptomeningeal carcinomatosis may be enrolled at the discretion of the Sponsor as long as the patient is stable and has received prior therapy indicated for leptomeningeal carcinomatosis for at least 4 weeks prior to entry.
3. For Phase 2a: History of previous cancer requiring therapy within the previous 3 years, except squamous cell or basal-cell carcinoma of the skin, or any in situ carcinoma that have been completely resected.
4. Incomplete recovery from any surgery prior to treatment.
5. Any of the following in the past 6 months: myocardial infarction, unstable angina, coronary/ peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication.
6. History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 milliseconds from ECGs performed at least 24 hours apart).
7. History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).
8. Known active infections (bacterial, fungal, viral including HIV positivity).
9. Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
10. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis.
11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
12. History of stroke in the past 12 months.
13. Peripheral neuropathy = Grade 1.
14. Require anti-epileptic treatment in the previous 4 weeks for seizure prophylaxis due to CNS metastases.
15. Pulmonary embolism in the past 3 months.
16. Require supplemental oxygen.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Locally advanced or metastatic solid tumors
MedDRA version: 17.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 100000004864
MedDRA version: 17.1 Level: LLT Classification code 10065143 Term: Malignant solid tumour System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: RXDX-101
Pharmaceutical Form: Capsule
INN or Proposed INN: Entrectinib
CAS Number: 1108743-60-7
Current Sponsor code: RXDX-101
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
INN or Proposed INN: Entrectinib
CAS Number: 1108743-60-7
Current Sponsor code: RXDX-101
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: Entrectinib
CAS Number: 1108743-60-7
Current Sponsor code: RXDX-101
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Secondary Objective: Phase 1 dose escalation.To assess:
- Safety profile of RXDX-101
- Pharmacokinetics
- Antitumor activity
- Assay methods to detect molecular alterations (as defined in Biomarker Assessments) and identify appropriate analytical cutoffs, and other relevant biomarker parameters that predict antitumor activity of RXDX-101
- Pharmacodynamics of RXDX-101 on molecular targets in tumor and surrogate tissue

Phase 2a segment .To assess:
-Progression-Free Survival
-Overall Survival
- Disease Control
- Duration of response
- Intracranial tumor response for patients with brain metastases
- Safety and tolerability of RXDX-101
- Assay methods to detect molecular alterations (as defined in Biomarker Assessments) and identify appropriate analytical cutoffs and other relevant biomarker parameters that predict antitumor activity of RXDX-101
- Pharmacodynamics of RXDX-101 on molecular targets in tumor and surrogate tissue
- Pharmacokinetics of RXDX-101 and metabolite in plasma

Main Objective: Primary Objective of Phase 1 Dose Escalation:
The primary objective of the Phase 1 dose escalation segment is to determine the first cycle dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and a biologically effective and recommended Phase 2 dose (RP2D) of RXDX-101 orally administered.

Primary Objective of Phase 2a Expansion:
The primary objective of the Phase 2a expansion cohorts is Objective Response (OR) defined as Complete Response (CR) and Partial Response (PR) at the RP2D of RXDX-101 orally administered.

Primary end point(s): - Phase I
DLTs,(dose-limiting toxicities) MTD (maximum tolerated dose) and RP2D (recommended Phase 2 dose)

- Phase 2
OR (Objective Response) defined as Complete Response (CR) and Partial Response (PR) according to RECIST v1.1.
Measured by tumour imaging

Timepoint(s) of evaluation of this end point: - Phase I
First cycle

- Phase 2
Scr; D42-C1; D28 all other cycles; EoT

Secondary Outcome(s)

Secondary end point(s): - Phase I
1. Adverse events
2. Clinical safety lab test (blood, urine)
3. Vital signs, weight performance
4. ECG
5. Physical examination
6. Pharmacokinetics (PK)
7. Objective Response (OR)
8. Progression-Free Survival (PFS)
9. Overall Survival (OS)
10. Disease Control (DC)
11. Duration of response (DOR)
12. Pharmacodynamics (PD)
13. CSF.

- Phase 2
1. Adverse events
2. Clinical safety lab test (blood, urine)
3. Vital signs, weight performance
4. ECG
5. Physical examination
6. Progression-Free Survival (PFS)
7. Overall Survival (OS)
8. Disease Control (DC)
9. Duration of response (DOR)
10. Intracranial tumour response
11. Pharmacodynamics (PD)
12. Pharmacokinetics (PK)
13. CSF

Timepoint(s) of evaluation of this end point: Ph I
1.V1-C1 to VFU
2.Scr; each D-C1,C2; D14, 28-each C;EoT
3.Scr; D1 to 28, 42-C1; D28-C2; D28-each C;EoT
4.Scr; D1,7,42-C1; D28-C2; D28-each C;EoT
5.Scr; each D-C1; D28-C2; D28 each C;EoT
6.D1,7,14,28, 35,42-C1; D28 each C.
7,8 Scr;D42, C1 D28 each C; D28 each C;EoT
9. 1st dose to death
10,11.Scr, D28-C2; D28 each C;EoT
12 D1 to 28-C1; C2D28;EoT
13 D21-C1.
Ph2
1.V1-C1 to VFU
2.Scr; D1 to 28-C1; each D-C2; D14, 28-each C;EoT
3.Scr; D1 to 28-C1; 28-C2; D28-each C;EoT
4.Scr; D1, 7,28-C1; D28-C2; D28-each C;EoT
5.Scr; D1 to 28-C1; D28-C2; D28 each C;EoT
6.Scr,D28-C2; D28 each C;EoT
7.1st dose to death
8,9,10. Scr, D28-C1; D28 each C;EoT
11.D1,7,14,28-C1; D28 each C;EoT
12.D1,7,14,28-C1; D28 each C.
13. D21-C1.

Secondary ID(s)

2014-001326-15-ES

RXDX-101-01

Source(s) of Monetary Support

Ignyta, Inc.