A Multi-arm Phase 1b Study of Talquetamab With Other Anticancer Therapies in Participants with Multiple Myeloma

Overview

The primary objectives of this study are to characterize the safety and tolerability of talquetamab combination regimens by assessing the incidence and severity of AEs, laboratory values, and the frequency and type of DLTs. A key secondary study objective is to evaluate antitumor activity of each treatment combination by assessing overall response as defined by IMWG 2016 response criteria, as well as duration of response and time to response.

 

 

This is an open-label, nonrandomized, multicenter, Phase 1b study to evaluate the safety and tolerability of

talquetamab combination regimens as well as to identify the safe dose(s) to take forward for subsequent

evaluation of these combination regimens in the treatment ofparticipants with multiple myeloma.

Description

Study Information

 

This is an open-label, nonrandomized, multicenter, Phase 1b study to evaluate the safety and tolerability of

talquetamab combination regimens as well as to identify the safe dose(s) to take forward for subsequent

evaluation of these combination regimens in the treatment ofparticipants with multiple myeloma.

 

Participants will be assigned to 1 of the following treatment regimens based on the participant’s disease

characteristics and prior treatment for multiple myeloma:

  • Treatment Regimen A (talquetamab + carfilzomib): Participants who have received ≥3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb.
  • Treatment Regimen B (talquetamab + daratumumab + carfilzomib): Participants who have received ≥3 prior lines of therapy, including a PI and an IMiD
  • Treatment Regimen C (talquetamab + lenalidomide): Participants who have received ≥2 prior lines of therapy, including a PI and an IMiD
  • Treatment Regimen D (talquetamab + daratumumab + lenalidomide): Participants who have received ≥3 prior lines of therapy, including a PI and an IMiD
  • Treatment Regimen E (talquetamab + pomalidomide): Participants who have received ≥2 prior lines of therapy, including a PI and lenalidomide

 

The study consists of a Screening Period (up to 28 days), a Treatment Period (until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or investigator or sponsor decision to discontinue treatment), and a Posttreatment Follow-up Period (up to 16 weeks).

 

 

Eligibility

Inclusion Criteria:

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

1. Be ≥18 years of age.

2. Sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study, including the requirement to provide information during the Posttreatment Follow-up Period. Consent must be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the participant’s disease. 

3. Have documented initial diagnosis of multiple myeloma according to IMWG diagnostic criteria (Appendix 5).

4. Criterion Modified per Amendment 1

   4.1 Meet treatment regimen-specific requirements as follows:

      a. Treatment Regimen A (talquetamab + carfilzomib): Participants with multiple myeloma who have received ≥3 prior lines of therapy,                      including a PI, an IMiD, and an anti-CD38 mAb

      b. Treatment Regimen B (talquetamab + daratumumab + carfilzomib): Participants with multiple myeloma who have received ≥3 prior lines              of therapy, including a PI and an IMiD

      c. Treatment Regimen C (talquetamab + lenalidomide): Participants with multiple myeloma who have received ≥2 prior lines of therapy,                    including a PI and an IMiD

      d. Treatment Regimen D (talquetamab + daratumumab + lenalidomide): Participants with multiple myeloma who have received ≥3 prior                  lines of therapy, including a PI and an IMiD

      e. Treatment Regimen E (talquetamab + pomalidomide): Participants with multiple myeloma who have received ≥2 prior lines of therapy,                  including a PI and lenalidomide

5. Have measurable disease at screening as defined by at least 1 of the following:

      a. Serum M-protein level ≥1.0 g/dL; or

      b. Urine M-protein level ≥200 mg/24 hours; or

      c. Light chain multiple myeloma: Serum Ig FLC ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. 

6. Have an ECOG performance status score of 0 or 1 at screening and immediately before the start of study treatment administration(Appendix 6)

7. Have clinical laboratory values meeting the following criteria during the Screening Period:

     Hematology

     Hemoglobin ≥ 8.0 g/dL (≥ 5 mmol/L) (without prior RBC transfusion within 7 days before the

     laboratory test; recombinant human erythropoietin use is permitted)

     Platelets ≥50×109/L (without transfusion support in the 7 days prior to the laboratory test)

     ANC ≥1.0×109/L (prior growth factor support is permitted but must be without support for 7 days if received G-CSF or GM-CSF or 14 days if         received peg-G-CSF)

 

     Chemistry

     AST and ALT ≤2.5×ULN

     Creatinine clearance ≥30 mL/min based upon Modified Diet in Renal Disease formula calculation (Appendix 7) or a 24-hour urine collection.

     Total bilirubin ≤1.5×ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case, direct bilirubin                 ≤1.5×ULN is required)

     Serum calcium corrected for albumin≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)

   

     ANC=absolute neutrophil count; ALT=alanine aminotransferase; AST=aspartate aminotransferase;

     G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte-macrophage colony-stimulating

     factor; peg-G-CSF=pegylated granulocyte colony-stimulating factor; RBC=red blood cell; ULN=upper limit of normal.

 

8. A woman of childbearing potential must have a negative highly sensitive serum (β-hCG) pregnancy test at screening and a negative urine or        serum pregnancy test within 24 hours before the start of study treatment administration.

9. A woman must be (as defined in Appendix 2):

    a. Not of childbearing potential, or

b. Of childbearing potential and

  •  practicing true abstinence;
  •  or have a sole partner who is vasectomized;
  •  or practicing at least 1 highly effective user-independent method of contraception (see Appendix 2). If hormonal contraception is used (eg, oral estrogen/progestin), a male or female condom with or without spermicide (eg, spermicidal foam/gel/film/cream/suppository) must also be used.

   o For participants enrolled in IMiD-containing regimens (Treatment Regimens C, D,

      and E), women of childbearing potential must be on 2 methods of reliable birth

      control simultaneously while receiving study treatment and until 100 days after last

      dose of study treatment: 1 highly effective form of contraception (tubal ligation,

      intrauterine device, hormonal [oral, injectable, transdermal patches, vaginal rings, or

      implants], or partner’s vasectomy), and 1 additional effective contraceptive method

      (male latex or synthetic condom, diaphragm, or cervical cap). For participants in

      Treatment Regimens C, D, or E who are of childbearing potential, see

      Section 6.8.3.1, for details regarding concomitant use of estrogen-containing

      products and IMiDs.

  • Agree to pregnancy testing (serum or urine) within 100 days after the last dose of study

           treatment.

      Note: If a participant’s childbearing potential or the risk of pregnancy changes after the

      start of the study, a woman must begin to use a highly effective method of contraception,

      as described in Appendix 2. If a participant’s reproductive status is questionable,

      additional evaluation should be considered. Potential interactions between hormonal

      contraception and talquetamab have not been formally studied. Therefore, it is unknown

      whether talquetamab may reduce the efficacy of the contraception method.

10. A man must wear a condom when engaging in any activity that allows for passage of ejaculate

      to another person during the study and for 100 days after the last dose of study treatment. Male

      participants should also be advised of the benefit for a female partner to use a highly effective

      method of contraception as condoms may break or leak.

11. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted

      reproduction during the study and for at least 100 days after the last dose of study treatment.

12. A man must agree not to donate sperm for the purpose of reproduction during the study and

     for a minimum of 100 days after receiving the last dose of study treatment.

13. Be willing and able to adhere to the lifestyle restrictions specified in this protocol

     (Section 5.3), including adherence to the applicable IMiD global PPP or local PPP/REMS

     program (see Appendix 2).

 

Eligibility

You may be eligible for this study if you meet the following criteria:

  • Conditions: multiple myeloma
  • Age: Between 18 Years - 85 Years
  • Gender: Male or Female

Inclusion Criteria:

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

1. Be ≥18 years of age.

2. Sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study, including the requirement to provide information during the Posttreatment Follow-up Period. Consent must be obtained prior to the initiation of any study-related tests or procedures that are not part of standard of care for the participant’s disease. 

3. Have documented initial diagnosis of multiple myeloma according to IMWG diagnostic criteria (Appendix 5).

4. Criterion Modified per Amendment 1

   4.1 Meet treatment regimen-specific requirements as follows:

      a. Treatment Regimen A (talquetamab + carfilzomib): Participants with multiple myeloma who have received ≥3 prior lines of therapy,                      including a PI, an IMiD, and an anti-CD38 mAb

      b. Treatment Regimen B (talquetamab + daratumumab + carfilzomib): Participants with multiple myeloma who have received ≥3 prior lines              of therapy, including a PI and an IMiD

      c. Treatment Regimen C (talquetamab + lenalidomide): Participants with multiple myeloma who have received ≥2 prior lines of therapy,                    including a PI and an IMiD

      d. Treatment Regimen D (talquetamab + daratumumab + lenalidomide): Participants with multiple myeloma who have received ≥3 prior                  lines of therapy, including a PI and an IMiD

      e. Treatment Regimen E (talquetamab + pomalidomide): Participants with multiple myeloma who have received ≥2 prior lines of therapy,                  including a PI and lenalidomide

5. Have measurable disease at screening as defined by at least 1 of the following:

      a. Serum M-protein level ≥1.0 g/dL; or

      b. Urine M-protein level ≥200 mg/24 hours; or

      c. Light chain multiple myeloma: Serum Ig FLC ≥10 mg/dL and abnormal serum Ig kappa lambda FLC ratio. 

6. Have an ECOG performance status score of 0 or 1 at screening and immediately before the start of study treatment administration(Appendix 6)

7. Have clinical laboratory values meeting the following criteria during the Screening Period:

     Hematology

     Hemoglobin ≥ 8.0 g/dL (≥ 5 mmol/L) (without prior RBC transfusion within 7 days before the

     laboratory test; recombinant human erythropoietin use is permitted)

     Platelets ≥50×109/L (without transfusion support in the 7 days prior to the laboratory test)

     ANC ≥1.0×109/L (prior growth factor support is permitted but must be without support for 7 days if received G-CSF or GM-CSF or 14 days if         received peg-G-CSF)

 

     Chemistry

     AST and ALT ≤2.5×ULN

     Creatinine clearance ≥30 mL/min based upon Modified Diet in Renal Disease formula calculation (Appendix 7) or a 24-hour urine collection.

     Total bilirubin ≤1.5×ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case, direct bilirubin                 ≤1.5×ULN is required)

     Serum calcium corrected for albumin≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)

   

     ANC=absolute neutrophil count; ALT=alanine aminotransferase; AST=aspartate aminotransferase;

     G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte-macrophage colony-stimulating

     factor; peg-G-CSF=pegylated granulocyte colony-stimulating factor; RBC=red blood cell; ULN=upper limit of normal.

 

8. A woman of childbearing potential must have a negative highly sensitive serum (β-hCG) pregnancy test at screening and a negative urine or        serum pregnancy test within 24 hours before the start of study treatment administration.

9. A woman must be (as defined in Appendix 2):

    a. Not of childbearing potential, or

b. Of childbearing potential and

  •  practicing true abstinence;
  •  or have a sole partner who is vasectomized;
  •  or practicing at least 1 highly effective user-independent method of contraception (see Appendix 2). If hormonal contraception is used (eg, oral estrogen/progestin), a male or female condom with or without spermicide (eg, spermicidal foam/gel/film/cream/suppository) must also be used.

   o For participants enrolled in IMiD-containing regimens (Treatment Regimens C, D,

      and E), women of childbearing potential must be on 2 methods of reliable birth

      control simultaneously while receiving study treatment and until 100 days after last

      dose of study treatment: 1 highly effective form of contraception (tubal ligation,

      intrauterine device, hormonal [oral, injectable, transdermal patches, vaginal rings, or

      implants], or partner’s vasectomy), and 1 additional effective contraceptive method

      (male latex or synthetic condom, diaphragm, or cervical cap). For participants in

      Treatment Regimens C, D, or E who are of childbearing potential, see

      Section 6.8.3.1, for details regarding concomitant use of estrogen-containing

      products and IMiDs.

  • Agree to pregnancy testing (serum or urine) within 100 days after the last dose of study

           treatment.

      Note: If a participant’s childbearing potential or the risk of pregnancy changes after the

      start of the study, a woman must begin to use a highly effective method of contraception,

      as described in Appendix 2. If a participant’s reproductive status is questionable,

      additional evaluation should be considered. Potential interactions between hormonal

      contraception and talquetamab have not been formally studied. Therefore, it is unknown

      whether talquetamab may reduce the efficacy of the contraception method.

10. A man must wear a condom when engaging in any activity that allows for passage of ejaculate

      to another person during the study and for 100 days after the last dose of study treatment. Male

      participants should also be advised of the benefit for a female partner to use a highly effective

      method of contraception as condoms may break or leak.

11. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted

      reproduction during the study and for at least 100 days after the last dose of study treatment.

12. A man must agree not to donate sperm for the purpose of reproduction during the study and

     for a minimum of 100 days after receiving the last dose of study treatment.

13. Be willing and able to adhere to the lifestyle restrictions specified in this protocol

     (Section 5.3), including adherence to the applicable IMiD global PPP or local PPP/REMS

     program (see Appendix 2).

 

Exclusion Criteria:

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Prior treatment with any therapy that targets GPRC5D.

2. Prior antitumor therapy as follows, in the specified time frame prior to the first dose of study treatment:

   a. Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an 

       invasive investigational medical device within 21 days or at least 5 half-lives, whichever is less.

   b. Gene-modified adoptive cell therapy (eg, CAR modified T-cells, NK cells) within 3 months.

   c. mAb treatment or bispecific T-cell redirector therapy for multiple myeloma within 21 days.

   d. Cytotoxic therapy within 21 days.

   e. PI therapy within 14 days.

   f. Immunomodulatory agent therapy within 7 days.

   g. Radiotherapy within 14 days. However, if palliative focal radiation is used, the participant is eligible irrespective of the end date of                         radiotherapy.

3. Live, attenuated vaccine within 4 weeks before the first dose of study treatment.

4. Non-hematologic toxicity from prior anticancer therapy that has not resolved to baseline levels

    or to Grade ≤1 (except alopecia [any grade] or peripheral neuropathy Grade ≤3).

5. Received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the

    14-day period before the start of study treatment administration (Appendix 9).

6. Received either of the following:

    a. An allogeneic SCT within 6 months before the first dose of study treatment. Participants

        who received an allogeneic transplant must be off all immunosuppressive medications

        during the 6 weeks before the start of study treatment administration without signs of

        graft-versus-host disease.

    b. An autologous SCT within 12 weeks before the start of study treatment administration.

7. Active CNS involvement or exhibition of clinical signs of meningeal involvement of multiple

    myeloma. If either is suspected, brain MRI and lumbar cytology are required.

8. Active plasma cell leukemia (>2.0×109/L plasma cells by standard differential),

    Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly,

     endocrinopathy, M-protein, and skin changes), or primary amyloid light chain amyloidosis.

9. Known to be seropositive for human immunodeficiency virus.

10. Seropositive for HBV, defined by a positive test for HbsAg. Participants with resolved

      infection (ie, participants who are HbsAg negative but positive for hepatitis B core antibody

      [anti-HBc] and/or positive for hepatitis B surface antibody [antiHBs]) must be screened using

       real-time PCR measurement of HBV DNA levels (Appendix 10). Those who are PCR positive

       will be excluded. EXCEPTION: Participants with serologic findings suggestive of HBV

       vaccination (antiHBs positivity as the only serologic marker) and a known history of prior

       HBV vaccination do not need to be tested for HBV DNA by PCR.

11. Active hepatitis C infection as measured by positive HCV-RNA testing. Participants with a

      history of HCV antibody positivity must undergo HCV-RNA testing.

12. Known allergies, hypersensitivity, or intolerance to any study treatment or their excipients

      (refer to the applicable Investigator’s Brochure and package inserts).

13. Any serious underlying medical condition, such as:

      a. Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection.

      b. Active autoimmune disease requiring systemic immunosuppressive therapy within

          6 months before start of study treatment. EXCEPTION: Participants with vitiligo, type I

          diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical

          symptoms and laboratory testing are eligible regardless of when these conditions were

          diagnosed.

       c. Disabling psychiatric conditions (eg, ongoing alcohol or drug abuse), severe dementia, or

           altered mental status.

       d. Any other issue that would impair the ability of the participant to receive, absorb, or

           tolerate the planned treatment at the study site, to understand informed consent, or any

           condition for which, in the opinion of the investigator, participation would not be in the

           best interest of the participant (eg, compromise well-being) or that could prevent, limit,

           or confound the protocol-specified assessments.

14. History of stroke or seizure within 6 months prior to the first dose of study treatment.

15. Any of the following cardiac conditions:

      a. New York Heart Association stage III or IV congestive heart failure.  

      b. Myocardial infarction, unstable angina, or coronary artery bypass graft ≤6 months prior

          to enrollment.

      c. History of clinically significant ventricular arrhythmia or unexplained syncope not

          believed to be vasovagal in nature or due to dehydration.

      d. History of severe nonischemic cardiomyopathy.

      e. Treatment Regimen A (tal-cfz) and Treatment Regimen B (tal-dara-cfz) only:

          transthoracic echocardiography showing LVEF <40%.

16. Pregnant or breastfeeding or planning to become pregnant while enrolled in this study or

      within 100 days after the last dose of study treatment.

17. Planning to father a child while enrolled in this study or within 100 days after the last dose of

      study treatment.

18. Major surgery within 2 weeks of the first dose of study treatment, or will not have fully

      recovered from surgery, or has surgery planned during the time the participant is expected to

      be treated in the study or within 2 weeks after the last dose of study treatment administration.

      Note: participants with planned surgical procedures to be conducted under local anesthesia

      may participate.

19. Treatment Regimen B (taldara-cfz) and Treatment Regimen D (taldaralen) only: Has

      either of the following:

      a. COPD with FEV1<50% of predicted normal. Note that FEV1 testing is required for

          participants suspected of having COPD, and participants must be excluded if FEV1 is

          <50% of predicted normal; testing done as standard of care within 6 months of the first

          dose of study treatment is acceptable for this criterion.

       b. Moderate or severe persistent asthma within the past 2 years (see Appendix 11), or

           uncontrolled asthma of any classification. Note: participants who currently have

           controlled intermittent asthma or controlled mild persistent asthma are allowed to

           participate in the study. 

Updated on 20 Nov 2022 . Study ID: TX11498
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