CRB-601-01 is a three-part interventional study which aims to:
- To determine the maximum tolerated dose (MTD) and pharmacologically active dose
range (PADR) for CRB-601 administered as a monotherapy in patients with select
relapsed/refractory solid tumors who have progressed after at least one line of
therapy
- To determine the optimized dose for CRB-601 when administered within the PADR in
combination with anti-programmed (cell) death ligand 1 (anti-PD-(L)1) therapy ( in
patients with select relapsed/refractory solid tumors who have progressed after at
least one line of therapy
- To determine the optimized dose for CRB-601 when administered within the PADR in
combination with anti-PD(L)-1 therapy in patients with select relapsed/refractory
solid tumors who have progressed after at least one line of therapy
The study will be run in 3 parts (A-C), run sequentially.
Part A Dose Escalation
Part A is designed to evaluate the safety, tolerability, and determine the MTD of CRB-601
administered as monotherapy in participants with select relapsed/refractory solid tumors
that are known to express avb8 integrin. All participants will have had disease
progression (PD) after at least one line of therapy or have no other standard therapy of
proven clinical benefit currently available or be recommended based on the investigator's
individual risk-benefit assessment for the participant.
In Part A, doses will be escalated following the standard Bayesian Optimal Interval
Design (BOIN) to determine the MTD and PADR or CRB-601. Three (3) dose groups treated on
a 28 cycle with dosing every 2 weeks (Q2W) are predetermined. The target toxicity level
is 0.3, the maximum number of participants that can be enrolled at each dose level is 12
participants and the maximum sample size of the BOIN design is 36. Determination of
dose-limiting toxicities (DLT) will be based on toxicities observed during the DLT
observation period (first 28-days or Cycle 1). Dose escalation /de-escalation decisions
are made on the basis of occurrence of DLT.
Part B Combination Safety Lead-in and Signal Seeking
Part B is designed to assess the safety and tolerability of CRB-601 combined with
anti-PD(L)-1 therapy. There will be two distinct phases to Part B, a safety lead-in phase
with a two-step dose-escalation and an Expansion Phase to seek efficacy signals in select
solid tumors. The following cohorts will be initiated:
Safety Lead-in
- A cohort of 10 participants with select tumor-types (10 participants at a low-dose
as selected in Part A) in combination with anti-PD(L)-1 at the recommended dose and
schedule.
- A second cohort of 10 participants will be treated with CRB-601 (10 participants at
a high-dose as selected in Part A) in combination with anti-PD(L)-1 at the
recommended dose and schedule.
Additional participants with select tumor-types showing preliminary efficacy will be
enrolled in an expansions phase.
Part C Dose Optimization
Part C will follow a time-to-event Bayesian optimal Phase 2 (TOP Bayesian) study design
developed for cancer immunotherapy. The aim of dose optimization is to determine the
recommended Phase 2 dose (RP2D) by evaluating the efficacy of CRB-601 in combination with
anti-PD(L)-1 (in terms of objective response rate [ORR]) when administered at two dose
levels in a tumor-type selected based on preliminary efficacy observed in Part A and B.
Participants will be randomized into one of two dose levels (low-dose CRB-601 group and
high-dose CRB- 601 group) of 12-20 participants. In each arm, eligible participants will
receive CRB-601 in combination with anti-PD(L)-1and be monitored for safety and efficacy.
For all enrolled participants (Parts A to C), study intervention will continue until any
of the pre-defined criteria for discontinuation of study intervention are met, including
intolerable toxicity, death, withdrawal of consent for study intervention, start of a new
anti-cancer therapy, or investigator determined PD according to RECIST 1.1 or symptomatic
deterioration attributed to PD.
General
In all parts, tumor response will be evaluated by the investigator according to RECIST
v1.. During the post-treatment follow-up period, only participants who had discontinued
study intervention for reasons other than PD or start of a new anti-cancer therapy (e.g.,
due to toxicity) will undergo tumor assessments. In these participants, tumor assessments
will continue until death, confirmed radiographic PD according to RECIST v1.1,
symptomatic deterioration attributed to PD, initiation of a subsequent anti cancer
therapy, withdrawal of consent for the study or any of the other pre defined criteria for
withdrawal from the study are met, whichever occurs first. All discontinued participants
(with the exception of the reason of death) will be followed for 3 months for
immune-related adverse events (irAEs) unless consent is refused in writing by the
participant. Lesions selected for on-treatment biopsy, will be omitted from tumor
assessments by RECIST v1.1. Clinical and laboratory adverse events (AEs) will be reported
and graded according to the National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE) v5.0. Guidelines for dose interruptions (e.g., for toxicity)
are included in the protocol.
Biomarkers will also be measured. Collection of off- and on-treatment biopsies in Parts A
to C are considered mandatory, unless agreed with the sponsor. Fresh tumor biopsies or
archival tumor formalin fixed paraffin embedded (FFPE) samples are acceptable for
baseline evaluation, and on-treatment samples will be collected on C2D15. Blood samples
for biomarker and cytokine/chemokine assessments will also be collected.
