| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic solid tumors |
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| E.1.1.1 | Medical condition in easily understood language |
Cancer that arises from organs and solid tissues which has spread to other organs
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
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| E.2.2 | Secondary objectives of the trial |
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
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (ECOG) performance status (PS) ≤ 2.
11. Adult patients (age ≥18).
12. Life expectancy of at least 3 months.
13. Baseline laboratory values fulfilling the study requirements.
14. Females of child-bearing potential must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. Females of childbearing potential must agree to avoid pregnancy during the study and agree upon the use of effective contraceptive methods (hormonal or barrier method of birth control, or abstinence) prior to study entry, for the duration of study participation and in the following 90 days after discontinuation of study treatment. Men with partner(s) of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 30 days after receiving study drug and use appropriate barrier contraception or abstinence.
15. Capability to swallow capsules intact (without chewing, crushing, or opening).
16. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
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|
| E.4 | Principal 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. |
|
| E.5 End points |
| E.5.1 | 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
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Phase I
First cycle
- Phase 2
Scr; D42-C1; D28 all other cycles; EoT
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|
| E.5.2 | 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 |
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| E.5.2.1 | 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Italy |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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