Carcinoid, Carcinoid Intestine Tumor, Carcinoid Syndrome, Carcinoid Syndrome Diarrhea, Carcinoid Tumor, Carcinoid Tumor of Cecum, Carcinoid Tumor of Ileum, Carcinoid Tumor of Liver, Carcinoid Tumor of Pancreas
Conditions
Keywords
Neuroendocrine tumor, Paltusotine, CRN00808, Carcinoid syndrome, Lanreotide, Octreotide, Somatostatin agonist
Brief summary
The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and exploratory dose response of paltusotine treatment in subjects with carcinoid syndrome. This study consists of a Randomized Treatment Phase followed by an Open-Label Extension (OLE) Phase.
Detailed description
This is a Phase 2, randomized, open-label, parallel-group, multicenter study designed to evaluate the safety, pharmacokinetics, and efficacy of paltusotine treatment in subjects with carcinoid syndrome. The study was conducted in 2 parts: a Randomized Treatment Phase (RTP) which is completed, and an Open-label Extension (OLE) Phase which is still ongoing. The RTP consisted of paltusotine treatment for 8 weeks. Subjects who completed the RTP were eligible to enter the OLE Phase at the recommendation of the Investigator. In the ongoing OLE Phase, paltusotine is being administered for a further 102 weeks. The total duration of paltusotine treatment for the combined RTP and OLE Phase is up to 110 weeks (28 months).
Interventions
DRUGRandomized: 40 mg Paltusotine
Two 20 mg tablets QD (Potential post-randomization dose escalation based on efficacy and acceptable tolerability: up to 80 mg)
DRUGRandomized: 80 mg Paltusotine
Four 20 mg tablets QD (Potential post-randomization dose escalation based on efficacy and acceptable tolerability: up to 120 mg)
Sponsors
Crinetics Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. Male or female subjects ≥18 years of age. 2. Documented carcinoid syndrome requiring medical therapy. 1. Not currently treated with somatostatin receptor ligands agonists for at least 12 weeks prior to screening and actively symptomatic. This can include treatment-naïve subjects. 2. Subjects currently treated with lanreotide, octreotide long acting release, or short acting octreotide (subcutaneous or oral) who are currently symptomatically controlled 3. Evaluable documentation of locally advanced or metastatic histopathologically confirmed well-differentiated neuroendocrine tumor (NET). Tumors must be Grade 1 (Ki-67 index \< 3%, or a mitotic count of \< 2 mitoses per 10 high-power fields, if the Ki-67 index is not available) or Grade 2 (Ki-67 index 3-20%, or a mitotic count of 2-20 mitoses per 10 high-power fields, if the Ki-67 index is not available) per the World Health Organization neuroendocrine neoplasm classification (Rindi and Inzani, 2020). Grade 3 tumors are not eligible. 4. No significant disease progression as assessed by the Investigator within the last 6 months before initiation of study drug dosing.
Exclusion criteria
1. Diarrhea attributed to any condition(s) other than carcinoid syndrome. 2. Uncontrolled/severe diarrhea associated with significant volume contraction, dehydration, or hypotension. 3. Requires second line treatments (eg, telotristat) for control of carcinoid syndrome symptoms. 4. Treatment with specific NET tumor therapy \<4 weeks before Screening (such as everolimus or sunitinib) or hepatic embolization, radiotherapy, peptide receptor radionuclide therapy (PRRT), and/or tumor debulking \<12 weeks before Screening. 5. History of another primary malignancy \<3 years prior to the date of first dose, except for adequately treated basal or squamous cell carcinoma of the skin, cancer of the breast or cervix in situ, previously treated or concurrent malignancy determined to be clinically stable and not requiring treatment. 6. Diabetes mellitus treated with insulin for less than 6 weeks prior to the study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | First dose of investigational medicine to End of Randomized Treatment Phase (8 weeks) | Incidence of TEAEs, including serious TEAEs and TEAEs leading to discontinuation; change from baseline to the EOR in safety parameters: clinical laboratory tests, physical exam findings, vital signs, 12-lead ECG, and 24-hour continuous cardiac monitoring (only for subjects on 120 mg dose). In addition to all-cause mortality, deaths were categorized by primary cause (e.g., cardiovascular) based on medical adjudication. Events were coded using MedDRA and summarized by treatment group, system organ class, and preferred term. TEAEs were reported per randomized arm. There were 2 randomized arms (40 mg and 80 mg paltusotine, with up-or down-dose titration permitted for symptom control). Results are analyzed based on the initially assigned randomization arm, regardless of the actual dose received. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) of Paltusotine | Measured at each visit (pre and post dose) up to Week 8 (i.e., End of Randomized Treatment Phase [EOR]) | Steady state trough levels by dose and visit for Randomized Treatment Phase (RTP). The "Overall Number of Participants Analyzed" displayed at the top of the PK summary table represents the total number of participants who received each dose at any point during the trial, factoring in dose titrations. PK results are summarized by actual dose taken right before the time of sample collection, rather than by randomized dose. Participants may be included in different dose groups for different visits due to dose titration. |
Countries
Argentina, Brazil, Canada, Mexico, Peru, Poland, United States
Participant flow
Recruitment details
In general, results are reported based on the dose assigned at randomization, regardless of the actual dose received.
Participants by arm
| Arm | Count |
|---|---|
| 40 mg Paltusotine Randomized: 40 mg paltusotine: Two 20 mg tablets QD (Potential post-randomization dose escalation based on efficacy and acceptable tolerability: up to 80 mg) | 18 |
| 80 mg Paltusotine Randomized: 80 mg paltusotine: Four 20 mg tablets QD (Potential post-randomization dose escalation based on efficacy and acceptable tolerability: up to 120 mg) | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | 40 mg Paltusotine | 80 mg Paltusotine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 9 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 9 Participants | 20 Participants |
| Age, Continuous | 58.6 years | 62.9 years | 60.8 years |
| Baseline Mean Daily Bowel Movements (/day) | 3.881 BMs per day STANDARD_DEVIATION 2.0398 | 3.343 BMs per day STANDARD_DEVIATION 1.3705 | 3.612 BMs per day STANDARD_DEVIATION 1.7343 |
| Baseline Mean Daily Flushing Criteria Episode (/day) | 2.325 FE per day STANDARD_DEVIATION 1.3219 | 2.413 FE per day STANDARD_DEVIATION 2.3313 | 2.369 FE per day STANDARD_DEVIATION 1.8683 |
| Body Mass Index (BMI) | 29.057 kg/m^2 STANDARD_DEVIATION 4.3181 | 28.609 kg/m^2 STANDARD_DEVIATION 10.8261 | 28.833 kg/m^2 STANDARD_DEVIATION 17.58 |
| Duration Since Carcinoid Syndrome Diagnosis (Months) | 102.566 months STANDARD_DEVIATION 82.0788 | 54.459 months STANDARD_DEVIATION 37.1727 | 78.513 months STANDARD_DEVIATION 67.3684 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 8 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Europe | 1 participants | 1 participants | 2 participants |
| Region of Enrollment South America | 8 participants | 7 participants | 15 participants |
| Region of Enrollment United States | 9 participants | 10 participants | 19 participants |
| Screening Group, n (%) Currently Treated with Lanreotide, Octreotide LAR, or Short-acting Octreotide | 13 Participants | 14 Participants | 27 Participants |
| Screening Group, n (%) Not Currently on SRLs or Naïve to SRLs | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Female | 8 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Male | 10 Participants | 7 Participants | 17 Participants |
| Symptomatic Entry Criteria Met - n (%) Bowel Movement and Flushing Criteria | 8 Participants | 3 Participants | 11 Participants |
| Symptomatic Entry Criteria Met - n (%) Bowel Movement Criteria Only | 6 Participants | 8 Participants | 14 Participants |
| Symptomatic Entry Criteria Met - n (%) Flushing Criteria Only | 4 Participants | 7 Participants | 11 Participants |
| Tumor Confirmation Method, n (%) CT Scan | 9 Participants | 13 Participants | 22 Participants |
| Tumor Confirmation Method, n (%) MRI | 9 Participants | 5 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 1 / 18 |
| other Total, other adverse events | 16 / 18 | 15 / 18 |
| serious Total, serious adverse events | 2 / 18 | 2 / 18 |
Outcome results
Primary
Safety - Incidence of Treatment-emergent Adverse Events (TEAEs)
Incidence of TEAEs, including serious TEAEs and TEAEs leading to discontinuation; change from baseline to the EOR in safety parameters: clinical laboratory tests, physical exam findings, vital signs, 12-lead ECG, and 24-hour continuous cardiac monitoring (only for subjects on 120 mg dose). In addition to all-cause mortality, deaths were categorized by primary cause (e.g., cardiovascular) based on medical adjudication. Events were coded using MedDRA and summarized by treatment group, system organ class, and preferred term. TEAEs were reported per randomized arm. There were 2 randomized arms (40 mg and 80 mg paltusotine, with up-or down-dose titration permitted for symptom control). Results are analyzed based on the initially assigned randomization arm, regardless of the actual dose received.
Time frame: First dose of investigational medicine to End of Randomized Treatment Phase (8 weeks)
Population: Safety Analysis Set included all randomized participants receiving ≥1 dose. TEAEs (reported per randomized arm) are defined as AEs from first to last dose date (end of RTP, or early term), plus 28 days (Safety follow up). Dose changes at Weeks 2 or 4 were allowed for symptom control (increase) or poor tolerability (decrease). Results are provided by randomized arms (40 mg and 80 mg paltusotine).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Treatment-Emergent Adverse Events (TEAE) | 16 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Drug Withdrawn | 0 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Related to CS Symptoms | 10 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Highest Severity of TEAE: Severe TEAE | 3 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Highest Severity of TEAE: Moderate TEAE | 6 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Highest Severity of TEAE: Mild TEAE | 7 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 2 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Treatment Related TEAE | 10 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Treatment Related Serious TEAE | 0 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Leading to Study Discontinuation | 1 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Leading to Actions Taken with Study Treatment: Dose Increased | 3 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Leading to Actions Taken with Study Treatment: Dose Decreased | 0 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Drug Interrupted | 3 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Dose Not Changed | 16 participants |
| 40 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Not Applicable | 2 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Drug Withdrawn | 1 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Treatment Related Serious TEAE | 0 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Treatment-Emergent Adverse Events (TEAE) | 15 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Dose Not Changed | 15 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Related to CS Symptoms | 9 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Leading to Study Discontinuation | 1 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Highest Severity of TEAE: Severe TEAE | 1 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Drug Interrupted | 2 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Highest Severity of TEAE: Moderate TEAE | 7 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Leading to Actions Taken with Study Treatment: Dose Increased | 1 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Highest Severity of TEAE: Mild TEAE | 7 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Actions Taken with Study Treatment: Not Applicable | 4 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 2 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | TEAE Leading to Actions Taken with Study Treatment: Dose Decreased | 2 participants |
| 80 mg Paltusotine | Safety - Incidence of Treatment-emergent Adverse Events (TEAEs) | Treatment Related TEAE | 13 participants |
Secondary
Pharmacokinetics (PK) of Paltusotine
Steady state trough levels by dose and visit for Randomized Treatment Phase (RTP). The Overall Number of Participants Analyzed displayed at the top of the PK summary table represents the total number of participants who received each dose at any point during the trial, factoring in dose titrations. PK results are summarized by actual dose taken right before the time of sample collection, rather than by randomized dose. Participants may be included in different dose groups for different visits due to dose titration.
Time frame: Measured at each visit (pre and post dose) up to Week 8 (i.e., End of Randomized Treatment Phase [EOR])
Population: The PK Analysis Set included all randomized participants with ≥1 paltusotine dose and ≥1 plasma measurement. Post-dose samples were taken 1-3 hrs after dosing, and steady-state troughs were assessed pre and post dose, through Week 8. Primary PK summaries were based on the RTP. Dose adjustments at Weeks 2 or 4 were allowed for symptom control (dose increase) or tolerability (dose decrease).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 4 (PRE-DOSE) | 68.2 ng/mL | Geometric Coefficient of Variation 179.1 |
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 1 (POST-DOSE) | 188 ng/mL | Geometric Coefficient of Variation 80.8 |
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 6 (POST-DOSE) | 261 ng/mL | Geometric Coefficient of Variation 108.6 |
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 4 (POST-DOSE) | 209 ng/mL | Geometric Coefficient of Variation 202.1 |
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 6 (PRE-DOSE) | 57.8 ng/mL | Geometric Coefficient of Variation 188.8 |
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 2 (POST-DOSE) | 217 ng/mL | Geometric Coefficient of Variation 90.5 |
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 2 (PRE-DOSE) | 61.4 ng/mL | Geometric Coefficient of Variation 153.5 |
| 40 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 8 - EOR (PRE-DOSE) | 63.3 ng/mL | Geometric Coefficient of Variation 122.1 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 4 (POST-DOSE) | 462 ng/mL | Geometric Coefficient of Variation 82.7 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 1 (POST-DOSE) | 360 ng/mL | Geometric Coefficient of Variation 103.3 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 2 (PRE-DOSE) | 193 ng/mL | Geometric Coefficient of Variation 83.5 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 2 (POST-DOSE) | 473 ng/mL | Geometric Coefficient of Variation 78.7 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 4 (PRE-DOSE) | 158 ng/mL | Geometric Coefficient of Variation 74.7 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 6 (PRE-DOSE) | 155 ng/mL | Geometric Coefficient of Variation 63.1 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 6 (POST-DOSE) | 532 ng/mL | Geometric Coefficient of Variation 89.4 |
| 80 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 8 - EOR (PRE-DOSE) | 165 ng/mL | Geometric Coefficient of Variation 44.5 |
| 120 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 4 (PRE-DOSE) | 218 ng/mL | Geometric Coefficient of Variation 0 |
| 120 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 8 - EOR (PRE-DOSE) | 201 ng/mL | Geometric Coefficient of Variation 69.1 |
| 120 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 6 (POST-DOSE) | 474 ng/mL | Geometric Coefficient of Variation 79 |
| 120 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 4 (POST-DOSE) | 545 ng/mL | Geometric Coefficient of Variation 184.5 |
| 120 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 2 (POST-DOSE) | 1240 ng/mL | Geometric Coefficient of Variation 0 |
| 120 mg Paltusotine | Pharmacokinetics (PK) of Paltusotine | WEEK 6 (PRE-DOSE) | 146 ng/mL | Geometric Coefficient of Variation 58.4 |