| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed / Refractory Metastatic or Advanced Solid Tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors which have spread in the body |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| 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 |
Part 1 (Phase I), dose escalation cohorts/Part 2 Group E
• To characterize the safety and tolerability of RVU120 as single agent in
patients with solid tumors
Part 2 (Phase II): safety expansion and efficacy groups
• To further evaluate the safety and tolerability of RVU120 as a single
agent in patients with selected tumor types
• To explore the anti-tumor activity of RVU120 as single agent in
patients with selected tumor types |
|
| E.2.2 | Secondary objectives of the trial |
Part 1 (Phase I), dose escalation cohorts/Part 2 Group E
• To determine the preliminary anti-tumor response to RVU120
• To determine the PK profile of RVU120
Part 2 (Phase II): safety expansion and efficacy groups
• To determine the PK profile of RVU120, including (in a subgroup of
patients) the effect of food |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for Part 1 and Part 2:
1. Age 18 years or older
2. Histologically confirmed and/or documented advanced or metastatic
tumors who have exhausted the available standard treatment(s) of the
respective country and/or progressing from at least one previous
systemic therapy and not eligible to further available therapy
3. At least one measurable or evaluable disease according to RECIST
v1.1 (Appendix 1)
4. Performance status of Eastern Cooperative Oncology Group (ECOG) 0-
2 (Appendix 3)
5. Estimated life expectancy of at least 12 weeks
6. Toxicities incurred as a result of previous anti-cancer therapy resolved
to ≤ Grade 1 (as defined by National Cancer Institute Common
Terminology Criteria for Adverse Events [NCI CTCAE] v5.0, Appendix 2),
except for alopecia, lymphopenia assessed as non-clinically significant,
sensory neurotoxicity and erectile dysfunction that could be ≤ Grade 2
7. At least a 4-week interval between the last received radiotherapy and
the first scheduled day of dosing with RVU120 (with the exception of
palliation radiotherapy which is allowed up to 2 weeks prior the first
scheduled day of dosing)
8. Complete recovery from major surgery (stable and < Grade 2 toxicity
sequela acceptable)
9. At least 2 weeks beyond high dose systemic corticosteroids (however,
low dose corticosteroids < 20 mg prednisone or equivalent daily are
permitted)
10. Laboratory values at Screening and /or at Day 1 Cycle 1 pre-dose:
a. Absolute neutrophil count ≥1.5 x 109/L without colony stimulating
factor support
b. Platelets > 100 x 109/L
c. Only for Part 1: Hemoglobin ≥9 g/dL (or ≥2.2 mmol/L) without red
blood cell transfusion within 4 weeks
d. Serum albumin ≥ 30g/L (3.0g/dL)
e. Total bilirubin <1.5 times the upper limit of normal (ULN)
f. Aspartate aminotransferase (AST ; SGOT) ≤3 x ULN; alanine
aminotransferase (ALT ;SGPT) ≤3 x ULN; (≤5 x ULN for patients with advanced solid tumors with liver metastases); Alkaline phosphatase ≤ 5
x ULN for patients with advanced solid tumors with bone or liver
metastases
g. Creatinine clearance ≥60 mL/min (Cockcroft-Gault formula Appendix
4)
h. Normal coagulation (elevated international normalized ratio [INR],
prothrombin time or activated partial thromboplastin time [APTT] <1.3 x
ULN acceptable)
11. Left ventricular ejection fraction> 50% by echocardiogram or
multiple gated acquisition (MUGA)
12. Able to provide an archival or fresh tumor biopsy sample at
Screening. For patients in Part 2, baseline tumor biopsy samples from
progressive disease lesions, where feasible, are required
13. For women of childbearing potential (WOCBP), a negative pregnancy
test must be confirmed before enrolment. WOCBP must commit to using
highly effective contraception during study participation and until 6
months after the last dose of study drug (see Appendix 5). Females must
also refrain from donating blood or egg (ovum) during the same timeperiod
14. For males, an effective barrier method of contraception must be used
during study participation until 6 months after the last dose of study
drug, if the patient is sexually active with a WOCBP. Males must also
refrain from donating blood or sperm during the same time-period
15. Ability to give written, informed consent prior to any study-specific
Screening procedures, with the understanding that the consent may be
withdrawn by the patient at any time without prejudice
16. Capable of understanding the mandated and optional protocol
requirements, is willing and able to comply with the study protocol
procedures and has signed the main informed consent document prior to
any study specific procedure. For any optional biopsy sampling (tissue
and/or blood) and long-term sample storage, additional consent is
required
17. Patients must have been off anti-cancer treatment and prohibited concomitant medications, for 4 weeks or 5 half-lives, whichever is shorter
Additional inclusion criteria for Part 2 Group A1
18. Histologically or cytologically confirmed TNBC of the mesenchymal or MSL subtype based on the most recent analyzed biopsy or other pathology specimen. Triple negative defined as <1% expression for estrogen receptor (ER) and progesterone receptor and negative for human epidermal growth factor receptor 2 (HER2) by a diagnostic immunochemistry (ICH) method.
Additional inclusion criterion for Part 2 Group A2
19. Histologically or cytologically confirmed TNBC other than the mesenchymal or MSL subtype based on the most recent analyzed biopsy or other pathology specimen. Triple negative defined as <1% expression for ER and progesterone receptor and negative for HER2 by a diagnostic ICH method |
|
| E.4 | Principal exclusion criteria |
General exclusion criteria for both Part 1 and Part 2:
Any of the following will exclude a patient from enrolment:
1. Active brain metastasis (patients with treated, non-progressive brain
metastases, off high-dose steroids [>20 mg prednisone or equivalent]
for at least 4 weeks can be enrolled in the trial)
2. Prior history of, or planned organ or hematopoietic stem cell
transplant
3. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or
viral infection and acute inflammatory conditions (including pancreatitis)
4. Known HIV infection with a CD4+ T-cell (CD4+) count of < 350
cells/μL or a history of AIDS defining opportunistic infection within the
past 12 months or on established antiretroviral therapy for < 4 weeks or
presenting with a viral load of > 400 copies/mL prior to enrollment or on
antiretroviral therapy or prophylactic antimicrobials that are expected to
cause significant drug-drug interactions or overlapping toxicities with
study treatment and cannot be changed to alternative agents
5. Known positive test of / or known active diagnosis of COVID-19 viral
infection
6. Ongoing significant liver disease such as cirrhosis, drug-induced liver
injury, active hepatitis or chronic persistent hepatitis B and/or C
•Positive serologic or polymerase chain reaction (PCR) test results for
acute or chronic hepatitis B virus (HBV) infection. Patients whose HBV
infection status cannot be determined by serologic test results must be
negative for HBV by PCR to be eligible for study participation
(www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf)
•Acute or chronic hepatitis C virus (HCV) infection. Patients who are
positive for HCV antibody must be negative for HCV by PCR to be eligible
for study participation
7. Impairment of gastrointestinal function or gastrointestinal disease
that may significantly alter the absorption of RVU120 (e.g., active
inflammatory bowel disease, ulcerative disease, malabsorption
syndrome, short bowel syndrome, uncontrolled nausea, persistent
vomiting or diarrhea)
8. Ongoing drug-induced pneumonitis
9. Concurrent participation in another investigational clinical trial
10. Taking any medications, herbal supplements or other substances
(including smoking) that are known to be strong inhibitors or strong
inducers or sensitive substrates of CYP1A2; with the exception of
antibiotics, antifungals, and antivirals that are used as the SOC or to
prevent or treat infections and other such drugs that are considered
absolutely essential for the care of the patient and no suitable or
available alternative could be found, with prior approval of the Sponsor
Study Medical Director (Appendix 6)
11. Mean measurement QTcF of >470 msec on triplicate
electrocardiograms (ECGs) performed within 5 minutes of each other,
using QTcF (Fredericia) formula
12. Currently taking drugs that are documented in the drug package
insert, to have risk of causing prolonged QTc or Torsades de Pointes
(TdP) (unless these can be changed to acceptable alternatives or
discontinued). Please also consult the following Credible Meds web page:
https://crediblemeds.org/index.php/login/dlcheck (Appendix 7)
(antibiotics, antifungals, and antivirals that are used as standard of care
or to prevent or treat infections and other such drugs that are
considered absolutely essential for the care of the patient and no
suitable or available alternative could be found, can be used with prior
approval by Sponsor Study Medical Director)
13. Patients with clinically significant cardiovascular disease. This
includes: myocardial infarction or unstable angina < 6 months prior to
Screening; New York Heart Association Grade III or greater congestive
heart failure (Appendix 8); cerebrovascular accident including transient ischemic attack within the past 6 months; uncontrolled hypertension;
serious or uncontrolled cardiac arrhythmia; personal history of TdP or syndrome of congenital QTc prolongation or QTc > 470 msec
14. Any other prior or current medical condition, intercurrent illness, surgical history, physical or ECG findings, laboratory abnormalities, or extenuating circumstance (e.g., alcohol or drug addiction) that, in the Investigator’s opinion, could jeopardize patient safety or interfere with the objectives of the study
15. Pregnant or breast-feeding females
Additional exclusion criteria for Part 2, Groups A1 and A2:
16. Prior history of malignancies other than TNBC, unless the patient has been free of the disease for > 5 years prior to Screening. Exceptions to the ≥5-year time limit include history of the following:
a. basal cell carcinoma of the skin;
b. non-metastatic squamous cell carcinoma of the skin;
c. carcinoma in situ of the cervix;
d. carcinoma in situ of the breast;
e. carcinoma in situ of the bladder;
f. incidental histological finding of prostate cancer (TNM stage T1a or T1b).
For all exclusion criteria please refer to the Protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 (Phase I), dose escalation cohorts/Part 2 Group E
• Frequency and nature of AEs, SAEs and DLTs
• Determination of the RP2D
Part 2 (Phase II): safety expansion and efficacy groups
• Frequency and nature of AEs and SAEs
The following will be assessed locally by RECIST v1.1, where applicable:
• ORR
• DoR
• PFS
• OS
• CBR
• CPR, when applicable |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For Part 1 and Part 2: Throughout the study period - from Screening Visit
to the Final Study Visit |
|
| E.5.2 | Secondary end point(s) |
Part 1 (Phase I), dose escalation cohorts/Part 2 Group E
The following will be assessed locally by RECIST v1.1, where applicable:
• ORR
• DoR
• PFS
• OS
• CBR
• CPR, when applicable
PK variables including:
• Cmax, Cmin, Tmax, t1/2, AUCtau
Part 2 (Phase II): safety expansion and efficacy groups
•Using population PK modelling and subgroup analysis, PK variables
including, as possible, Cmax, Cmin, Tmax, t1/2, and AUCtau |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For Part 1:
•End of cycle 3 plus end of cycle 6 and thereafter every fourth cycle
For Part 1 and Part 2:
Blood samples for the assessment of the PK profile of RVU120 and its
metabolites (as appropriate) in plasma will be taken at the specified
timepoints provided in Appendix 13 (see Table 10 for Part 1, Table 11 for
Part 2 Groups A - D, and Table 12 for Part 2 Group E). A PK blood sample
will also be taken as soon as possible when there is a > Grade 1
sign/symptom of acute infection/inflammation or a . Grade 1 troponin
increase. |
|
| 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 | Yes |
| 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
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Australia |
| China |
| United States |
| Czechia |
| France |
| Netherlands |
| Poland |
| Spain |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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