| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase 1: Advanced solid tumors, relapsed or refractory to standard therapy
Phase 2: non-small cell lung cancer, metastatic colorectal cancer, and other solid tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose Escalation Phase (Phase 1):
- To evaluate the overall safety and tolerability of JAB-21822 monotherapy
- To determine the maximum tolerated dose and a recommended Phase 2 dose of JAB-21822 monotherapy administered once daily in participants with relapsed or refractory solid tumors with KRAS G12C mutation
Dose Expansion Phase (Phase 2):
- To further evaluate preliminary antitumor activity, objective response rate, and duration of response of JAB-21822 monotherapy at the recommended Phase 2 dose in participants with relapsed and refractory non-small cell cancer and other solid tumors with KRAS G12C mutation, and in combination with cetuximab in metastatic colorectal cancer with KRAS G12C mutation |
|
| E.2.2 | Secondary objectives of the trial |
Dose Escalation Phase (Phase 1):
- To evaluate preliminary antitumor activity of various dose levels of JAB-21822 monotherapy in participants with relapsed and refractory solid tumors with KRAS G12C mutation
- To characterize the pharmacokinetic(s) profiles of JAB-21822 after a single dose and at steady state after multiple doses
Dose Expansion Phase (Phase 2):
- To determine progression-free survival, overall survival, time to response, and disease control rate
- To further assess the overall safety and tolerability of JAB-21822 at the recommended Phase 2 dose as monotherapy and in combination with cetuximab
- To further characterize the pharmacokinetic(s) profiles of JAB-21822 with sparse sampling using a population pharmacokinetic(s) analysis approach |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Written ICF must be signed and dated by the participant prior to the performance of any study-specific procedures, sampling, or analyses.
-≥18 years of age at the time of signing the ICF.
-ECOG performance status score of 0 or 1.
-Life expectancy ≥3 months.
-Participant must be able to provide an archived tumor sample or tumor tissue from a newly obtained biopsy from the tumor site which has not been previously irradiated.
-Histologically or cytologically confirmed solid tumors with KRAS G12C mutation by laboratories, which are either CLIA certified or recognized by local institution, and meets the following criteria:
Phase 1; Cohort A0
a.Have histologically or cytologically confirmed metastatic or locally advanced
solid tumor that is not a candidate for curative intervention.
b.Must have received at least 1 prior standard therapy for their tumor type and stage.
Phase 2; Cohort A1, A2 and Cohort B1, B2
A1:
a.Has histologically or cytologically confirmed diagnosis of unresectable Stage
IIIB or Stage IV NSCLC and is not a candidate for curative intervention.
b.Must have received a platinum-based therapy and an immune checkpoint
inhibitor unless such therapies are contraindicated or not available to the participant or the participant refused them. No more than 4 previous systemic regimens for the metastatic disease are allowed.
c.Participant with actionable mutations must have received appropriate targeted therapies available per local standard unless such therapies are contraindicated or not available to the participant or the participant refused them. No more than 3 previous systemic regimens for the metastatic disease are allowed.
d.Had received adjuvant or neoadjuvant chemotherapy and had
recurrence/progression on or within 6 months of completion of the therapy is
allowed to count the therapy as 1 previous regimen for the metastatic disease.
e.KRAS G12C inhibitors naïve.
A2:
a.KRAS G12C inhibitors naïve.
For mCRC:
b.Have histologically or cytologically confirmed mCRC that is not a candidate
for curative intervention.
c.Have received no more than 4 prior systemic regimens of standard therapy for mCRC per local treatment standard deemed to be appropriate by the
investigator unless such therapies are contraindicated, intolerable, or the
participant refused them.
d.Systemic regimens should include a fluoropyrimidine, irinotecan, and oxaliplatin.
e.For mCRC participants with MSI-H disease, must have prior systemic
regimens with checkpoint inhibitor unless such are contraindicated or not available to the participant or the participant refused them.
f.Participant who had received adjuvant or neoadjuvant chemotherapy and had recurrence/progression on or within 6 months of completion of the therapy is allowed to count the therapy as 1 previous regimen for the metastatic disease.
For all other solid tumors:
g.Have histologically or cytologically confirmed metastatic or locally advanced
solid tumor except NSCLC that is not a candidate for curative intervention.
h.Must have received at least 1 prior standard therapy for their tumor type and stage.
Cohort B:
a.Cohort B:
i.B1: KRAS G12C inhibitors naïve mCRC.
ii.B2: KRAS G12C inhibitors treated mCRC.
b.Have histologically or cytologically confirmed mCRC that is not a candidate
for curative intervention.
c.Has received no more than 4 prior systemic regimens of standard therapy for mCRC per local treatment standard deemed to be appropriate by the
investigator unless such therapies are contraindicated, intolerable, or the
participant refused them.
d.Systemic regimens should include a fluoropyrimidine, irinotecan, and oxaliplatin. No prior use of EGFR inhibitors.
e.For mCRC participants with MSI-H disease, must have prior systemic
regimens with checkpoint inhibitor unless such therapies are contraindicated or not available to the participant or the participant refused them.
f.Participant who had received adjuvant or neoadjuvant chemotherapy and had recurrence/progression on or within 6 months of completion of the therapy is allowed to count the therapy as 1 previous regimen for the metastatic disease.
-At least 1 measurable lesion as defined by RECIST v1.1.
- Women of childbearing potential must have a negative serum pregnancy test prior to study entry. Women of nonchildbearing potential must have had at least 12 continuous months of natural amenorrhea and an appropriate clinical profile, or have had surgical bilateral oophorectomy, hysterectomy, or bilateral tubal ligation >6 weeks prior to Screening.
-Male or female participants: Male participants with female partners of childbearing potential and female participants of childbearing potential are required to use 2 forms of acceptable contraception, including 1 barrier method, during their participation in the study and for 3 months following the last dose of JAB-21822 or 2 months following the last dose of cetuximab, whichever is longer, for Cohort B1 and B2. |
|
| E.4 | Principal exclusion criteria |
-Participant has a history of solid tumor or hematological malignancy that is histologically distinct from the cancers under study, except for cervical carcinoma in situ, superficial noninvasive bladder tumors, breast ductal carcinoma in situ, prostatic intraepithelial neoplasia without evidence of prostate cancer, or curatively treated Stage I nonmelanoma skin cancer.
-Participant has known serious allergy to cetuximab (Cohort B1 and B2 only) or to a G12C inhibitor (Cohort A0 and B2 only).
-Participant has brain or spinal metastases except if treated by surgery, surgery plus radiotherapy or radiotherapy alone, with no evidence of radiographic progression or hemorrhage for at least 28 days before the start of treatment with the study drugs, and if applicable, on stable dose of systemic corticosteroids for at least 28 days before the start of treatment with the study drugs.
-Active infection requiring systemic treatment at the start of treatment in this trial.
-Participants testing positive for HIV are NOT excluded from this study, but HIV positive participants must meet certain criteria.
-Has active HBV or HCV.
Note:Participants with HBV who have controlled infection (serum HBV DNA PCR that is below the limit of detection) are permitted. Participants with controlled infections must undergo periodic monitoring of HBV DNA.
Note:Participants who are HCV antibody positive who have controlled infection may be enrolled into the study. Participants with controlled infections must undergo periodic monitoring of HCV RNA by their treating physician.
-History (≤6 months before the start of treatment) of any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator and sponsor, could affect the participant’s participation in the study.
-History (≤6 months before the start of treatment with the study drugs) of any of the following: acute myocardial infarction, unstable angina pectoris, coronary artery bypass graft, or cerebrovascular accident.
-Participants who have impaired cardiac function or clinically significant cardiac
diseases.
-Participants with QT interval >470 msec at Screening using QTcF, determined as the mean of 3 QTcF values from the screening triplicate ECG.
-Participants experiencing unresolved Grade >1 toxicity before the start of treatment with the study drug except for hair loss (alopecia) and stable Grade 2 toxicities (stable defined as more than 3 months, if permitted by the investigator and medical monitor).
-Women who are pregnant or breast-feeding.
-Has received or will receive a live vaccine within 30 days prior to the first
administration of study medication. Seasonal flu vaccines that do not contain live vaccine are permitted.
-Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
-History of an allogeneic bone marrow or solid organ transplant.
-Use of systemic anticancer agent or investigational drug is prohibited ≤28 days for biologics and IV chemotherapy, or ≤21 days or 5 half-lives (whichever is longer) for small molecules prior to the first dose of JAB-21822.
-History of radiation therapy ≤14 days prior to the first dose of study drug.
-Prophylactic administration of G-CSF, filgrastim, pegfilgrastim, blood transfusion, platelet packets, and erythropoietin are not allowed during ≤4 weeks before the start of treatment and during Cycle 1 of the Dose Escalation Phase.
-Use of drugs known to be moderate or strong CYP3A4 inhibitors or inducers or
sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index is prohibited ≤14 days or 5 half-lives, whichever is longer, before the start of treatment with the study drug until the EOT visit. Some of these medications may be allowed at the investigator’s discretion after approval by the medical monitor.
-Use of herbal drugs and supplements known to be moderate or strong CYP3A4 inhibitors or inducers or sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or have another potential for clinically significant interaction with JAB-21822 are prohibited ≤14 days or 5 half-lives, whichever is longer, before the start of treatment with the study drug until the EOT visit.
-History (≤28 days before the start of treatment with the study drugs) of major surgery or trauma or likelihood to require surgery at any time until the permanent discontinuation of treatment (the significance will be determined by the investigator after consultation with the medical monitor).
-History (14 days or 5 half-lives, whichever is longer, before the start of treatment with the study drugs) of medications with known risk of Torsades de Pointes.
-Use of agents that suppress gastric acidity and agents that delay gastric emptying within 3 days or 5 half-lives (whichever is longer) prior to start of treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation Phase (Phase 1):
- Safety and tolerability of repeated cycles from first drug administration up to the end of the follow-up period
o Incidence, nature, and severity of treatment-emergent adverse events, treatment-related adverse events, and death per National Cancer Institute
Common Terminology Criteria for Adverse Events Version 5
- Treatment-emergent changes in clinical laboratory measurements, electrocardiogram findings, vital signs, Eastern Cooperative Oncology Group performance status, and physical examination findings
- Number and proportion of participants who experience at least 1 dose-limiting toxicity during the first 21 days of treatment
Dose Expansion Phase (Phase 2):
- Objective response rate defined as the percentage of participants with partial response or complete response based on Response Evaluation Criteria in Solid Tumors Version 1.1
- Duration of response |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Dose Escalation phase: Number of participants with dose limiting toxicities; Time Frame: At the end of Cycle 1
-Dose Escalation and Dose Expansion phase: Number of participants with adverse events; Time Frame: Up to 4 years; Patients will be assessed for incidence and severity of adverse events according to NCI-CTCAE criteria
-Dose Expansion phase: Overall response rate; Time Frame: Up to 4 years - from baseline to RECIST confirmed Progressive Disease
-Dose Expansion phase: Duration of response; Time Frame: Up to 4 years; DOR is defined as the time from the participant's initial objective response (CR or PR) to disease progression per CTCAE v1.1 or death due to any cause, whichever occurs first |
|
| E.5.2 | Secondary end point(s) |
Dose Escalation Phase (Phase 1):
- Objective response rate defined as the percentage of participants with partial response or complete response based on RECIST v1.1
- disease control rate, time to response, duration of response, and progression-free survival
- PK parameters of JAB-21822 including, but not limited to, Cmax, tmax, Ctrough, AUC0-τ, AUC0-t, AUC0-inf, t½, CL/F, Vz/F, Rac Cmax, and Rac AUC
Dose Expansion Phase (Phase 2):
- progression-free survival and time to response
- overall survival
- disease control rate
- Safety and tolerability of repeated cycles from first drug administration up to the end of the follow-up period
o Incidence, nature, and severity of treatment-emergent adverse events, treatment-related adverse events, and death per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5
- Treatment-emergent changes in clinical laboratory measurements, ECG findings, vital signs, Eastern Cooperative Oncology Group performance status, and physical examination findings
-PK parameters of JAB-21822 and potential factors (covariates) that impact the PK parameters |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Dose Escalation and Dose Expansion phase: Peak Plasma Concentration (Cmax); Time Frame: Up to 4 years
-Dose Escalation and Dose Expansion phase: Area under the plasma concentration versus time curve; Time Frame: Up to 4 years
-Dose Escalation phase: Overall response rate; Time Frame: Up to 4 years - from baseline to RECIST confirmed Progressive Disease
-Dose Escalation phase: Duration of response; Time Frame: Up to 4 years
-Dose Escalation and Dose Expansion phase: Disease Control Rate; Time Frame: Up to 4 years
-Dose Escalation and Dose Expansion phase: Progression-free survival; Time Frame: Up to 4 years |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| 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 | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Israel |
| United States |
| Hungary |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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