Participants received a combination of MK-1966 (Days 1 and 21) and SD-101 (Days 1, 8, 15 and Day 22) in Part A of the study (approximately 21 days). Participants were to continue in one of two expansion cohorts (Part B or C) and receive up to 8 cycles of treatment (approximately 24 weeks). Each cycle was 21 days.

Participants were to receive the MTD/MAD of MK-1966 and SD-101 established in Part A for up to 7 additional treatment cycles with MK-1966 and up to 6 additional treatment cycles with SD-101. Each cycle was to be 21 days.

Participants were to receive the MTD/MAD of MK-1966 and SD-101 established in Part A for up to 7 additional treatment cycles with MK-1966 and 6 additional treatment cycles with SD-101. Each cycle was to be 21 days.

MK-1966 administered as an intravenous (IV) infusion

MK-1966

SD-101 administered as an intratumoral (IT) injection

SD-101

Medical Director

This was a non-randomized, open-label study of MK-1966 used in combination with SD-101 in the treatment of advanced malignancies. The study included an initial Dose Evaluation phase (Part A) to determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) by evaluating Dose Limiting Toxicities (DLTs) of four dose combinations of MK-1966 and SD-101. Following determination of the MTD/MAD, approximately 20 participants each were to be enrolled in two expansion cohorts (Parts B or C) to confirm/refine the MTD/MAD. The study was terminated by the Sponsor before enrollment into Part A concluded and before enrollment into Parts B and C began.

Dose Evaluation of MK-1966 in Combination With SD-101 in Participants With Advanced Malignancies (MK-1966-001)

A Phase 1/1b Trial of MK-1966 in Combination With SD-101 in Subjects With Advanced Malignancies

https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

The occurrence of any of the following toxicities during Cycle 1 (Days 1-21), if assessed by the Investigator to be possibly, probably or definitely related to MK-1966 or SD-101, was considered a DLT:

1. Grade (Gr) 4 non-hematologic toxicity;
2. Gr 4 hematologic toxicity lasting \>7 days, except thrombocytopenia: \*Gr 4 thrombocytopenia of any duration; \*Gr 3 thrombocytopenia if associated with bleeding;
3. Gr 3 non-hematologic toxicity lasting \>3 days despite optimal supportive care;
4. Any Gr 3 or Gr 4 non-hematologic laboratory abnormality, if: medical intervention is required OR abnormality leads to hospitalization OR abnormality persists for \>1 week;
5. Febrile neutropenia Gr 3 or Gr 4;
6. Any drug-related AE which caused participant to discontinue study drug during Cycle 1
7. Gr 5 toxicity; or
8. Delay in initiation of Cycle 2 for \>2 weeks due to study drug-related toxicity. The percentage of participants who experienced a DLT during Cycle 1 is presented.

An AE was defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study drug or protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study drug, was also an AE. The number of participants who experienced as AE is presented.

The number of participants who discontinued study drug due to an AE is presented.

Merck Sharp & Dohme LLC

The safety analysis population consisted of all participants who received ≥1 dose of study drug.

Per protocol, progression of cancer under study was not considered an AE unless related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.

Participants received a combination of MK-1966 70 mg intravenously (IV) (on Day 1 of each 3-week cycle for up to 8 cycles) and SD-101 1 mg intratumorally (IT) (on Days 1, 8 and 15 of Cycle 1, and then on Day 1 of up to 7 additional 3-week cycles) in Part A of the study. Participants were then to continue in one of two expansion cohorts (Part B or C) and were to receive up to 8 cycles of treatment on Day 1 of each 3-week cycle (approximately 24 weeks), but the study was terminated by the Sponsor prior to completion of Part A enrollment and prior to initiation of Parts B or C enrollment.

MK-1966 70 mg+SD-101 1 mg

Participants received a combination of MK-1966 70 mg IV (on Day 1 of each 3-week cycle for up to 8 cycles) and SD-101 4 mg IT (on Days 1, 8 and 15 of Cycle 1, and then on Day 1 of up to 7 additional 3-week cycles) in Part A of the study. Participants were then to continue in one of two expansion cohorts (Part B or C) and were to receive up to 8 cycles of treatment on Day 1 of each 3-week cycle (approximately 24 weeks), but the study was terminated by the Sponsor prior to completion of Part A enrollment and prior to initiation of Parts B or C enrollment.

MK-1966 70 mg+SD-101 4 mg

Participants received a combination of MK-1966 210 mg IV (on Day 1 of each 3-week cycle for up to 8 cycles) and SD-101 4 mg IT (on Days 1, 8 and 15 of Cycle 1, and then on Day 1 of up to 7 additional 3-week cycles) in Part A of the study. Participants were then to continue in one of two expansion cohorts (Part B or C) and were to receive up to 8 cycles of treatment on Day 1 of each 3-week cycle (approximately 24 weeks), but the study was terminated by the Sponsor prior to completion of Part A enrollment and prior to initiation of Parts B or C enrollment.

MK-1966 210 mg+SD-101 4 mg

Participants received a combination of MK-1966 700 mg IV (on Day 1 of each 3-week cycle for up to 8 cycles) and SD-101 4 mg IT (on Days 1, 8 and 15 of Cycle 1, and then on Day 1 of up to 7 additional 3-week cycles) in Part A of the study. Participants were to continue in one of two expansion cohorts (Part B or C) and were to receive up to 8 cycles of treatment on Day 1 of each 3-week cycle (approximately 24 weeks), but the study was terminated by the Sponsor prior to completion of Part A enrollment and prior to initiation of Parts B or C enrollment.

MK-1966 700 mg+SD-101 4 mg

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

The study was terminated early due to business reasons.

Senior Vice President, Global Clinical Development

The DLT evaluable population consisted of all participants who completed study drug in Cycle 1 or discontinued study drug during Cycle 1 due to a DLT.

Percentage of Participants With a Dose Limiting Toxicity (DLT)

The safety analysis population consisted of all participants who received ≥1 dose of study drug.

Number of Participants With Adverse Events (AEs)

Number of Participants Discontinuing Study Drug Due to AEs

Overall Study

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anticonvulsants

Central Nervous System Depressants

Psychotropic Drugs

Anti-Infective Agents

Cyclophosphamide

Fluorouracil

Epirubicin

Valproic Acid

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Neurotransmitter Agents

Escalating doses of Valproic acid and one dose escalation step of epirubicin. Participants with breast cancer treated at the maximum tolerated dose, will also be treated with 5-fluorouracil and Cyclophosphamide.

Valproic acid

For breast cancer participants treated at MTD of Valproic acid and Epirubicin: 5-fluorouracil 500 mg/m\^2.

5-fluorouracil

For breast cancer participants treated at MTD of Valproic acid and Epirubicin: cyclophosphamide 500 mg/m\^2.

Cyclophosphamide.

Pamela Munster, MD

Adil Daud, MD

This is a Phase I dose escalation trial with escalating doses of Valproic acid and one dose escalation step of epirubicin. VPA will be escalated starting at a dose that is recommended for use as an anti-convulsant or to treat migraine headaches. Epirubicin will be given by infusion on day 3 after the last dose of divalproex. The study will determine the highest dose that these two drugs can be given together and as part of a multidrug regimen with 5-fluorouracil and cyclophosphamide.

This is a Phase I dose escalation trial with escalating doses of Valproic acid and one dose escalation step of epirubicin. VPA will be escalated starting at a dose that is recommended for use as an anti-convulsant or to treat migraine headaches. Recommended concentrations for seizure control is 15-60 mg/kg. Pharmacokinetic studies from healthy volunteers and patients suggested a linear increase in plasma concentrations. A daily dosing of 16 mg/kg divalproex (delayed-release VPA) resulted in a peak VPA plasma concentration of 127 μg/ml (\~0.9 mM) 27. The recommended Phase II dose of VPA was 60 mg/kg/d when given by a one-hour intravenous infusion twice daily for 5 days every three weeks.

Synergistic activity between VPA and epirubicin has been observed at 0.5 mM of VPA in our preclinical laboratory studies. Patients will receive an intravenous loading dose of VPA followed by divalproex in two daily doses for 5 doses. The loading dose of VPA will avoid a delay in peak plasma concentrations and excessive nausea. Epirubicin will be given by infusion on day 3 after the last dose of divalproex.

Once the MTD for this two drug regimen has been determined, the maximum tolerated dose will be determined as part of the FEC regimen (5-fluorouracil, epirubicin and cyclophosphamide).

Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies

To determine the pharmacokinetic profile of valproic acid and epirubicin in this combination.

To determine VPA effects on histone acetylation in peripheral blood mononuclear cells and VPA effects on histone acetylation and epirubicin induced DNA damage in biopsied tumors.

To determine the MTD for VPA and epirubicin in combination with 5-fluorouracil and cyclophosphamide commonly known as a regimen called FEC100.

To determine the utility of topo IIα and IIβ as predictive factors for response and their modulation as drug targets in patients with biopsied tumors and to document any responses to this combination.

MTD of Valproic acid in combination with Epirubicin. The maximum tolerated dose (MTD) will be defined as the highest dose level at which less than 2 out of 6 patients (\<33%) experience DLT in Cycle 1. A dose limiting toxicity (DLT) will be defined as any one of the specific adverse events (AEs) outlined in the protocol, occurring during Cycle 1 when considered related to therapy that is part of this study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Dose Evaluation of MK-1966 in Combination With SD-101 in Participants With Advanced Malignancies (MK-1966-001)	NCT02731742	Neoplasms, Adva...	MK-1966 SD-101	18 Years -	Merck Sharp & Dohme LLC
Phase I Trial of Valproic Acid and Epirubicin in Solid Tumor Malignancies	NCT00246103	Neoplasms, Adva...	Valproic acid Epirubicin 5-fluorouracil Cyclophosphamid...	18 Years -	H. Lee Moffitt Cancer Center and Research Institute

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